| 1. |
- Ahlin, Gustav, et al.
(författare)
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Structural requirements for drug inhibition of the liver specific human organic cation transport protein 1
- 2008
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 51:19, s. 5932-5942
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Tidskriftsartikel (refereegranskat)abstract
- The liver-specific organic cation transport protein (OCT1; SLC22A1) transports several cationic drugs including the antidiabetic drug metformin and the anticancer agents oxaliplatin and imatinib. In this study, we explored the chemical space of registered oral drugs with the aim of studying the inhibition pattern of OCT1 and of developing predictive computational models of OCT1 inhibition. In total, 191 structurally diverse compounds were examined in HEK293-OCT1 cells. The assay identified 47 novel inhibitors and confirmed 15 previously known inhibitors. The enrichment of OCT1 inhibitors was seen in several drug classes including antidepressants. High lipophilicity and a positive net charge were found to be the key physicochemical properties for OCT1 inhibition, whereas a high molecular dipole moment and many hydrogen bonds were negatively correlated to OCT1 inhibition. The data were used to generate OPLS-DA models for OCT1 inhibitors; the final model correctly predicted 82% of the inhibitors and 88% of the noninhibitors of the test set.
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| 2. |
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| 3. |
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| 4. |
- Ahlström, M. M., et al.
(författare)
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CYP2C9 structure-metabolism relationships: Optimizing the metabolic stability of COX-2 inhibitors
- 2007
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 50:18, s. 4444-4452
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Tidskriftsartikel (refereegranskat)abstract
- The cytochrome P450 (CYP) family is composed of a large group of monooxygenases that mediate the metabolism of xenobiotics and endogenous compounds. CYP2C9, one of the major isoforms of the CYP family, is responsible for the phase I metabolism of a variety of drugs. The aim of the present investigation is to use rational design together with MetaSite, a metabolism site prediction program, to synthesize compounds that retain their pharmacological effects but that are metabolically more stable in the presence of CYP2C9. The model compound for the study is the nonsteroidal anti-inflammatory drug celecoxib, a COX-2 selective inhibitor and known CYP2C9 substrate. Thirteen analogs of celecoxib were designed, synthesized, and evaluated with regard to their metabolic properties and pharmacologic effects. The docking solutions and the predictions from MetaSite gave useful information leading to the design of new compounds with improved metabolic properties.
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| 5. |
- Andersson, Ida E., 1982-, et al.
(författare)
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Probing Molecular Interactions within Class II MHC A(q)/Glycopeptide/T-Cell Receptor Complexes Associated with Collagen-Induced Arthritis.
- 2007
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 1520-4804 .- 0022-2623. ; 50:23, s. 5627-5643
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Tidskriftsartikel (refereegranskat)abstract
- T cells obtained in a mouse model for rheumatoid arthritis are activated by a glycopeptide fragment from rat type II collagen (CII) bound to the class II major histocompatibility complex A(q) molecule. We report a comparative model of A(q) in complex with the glycopeptide CII260-267. This model was used in a structure-based design approach where the amide bond between Ala(261) and Gly(262) in the glycopeptide was selected for replacement with psi[COCH2], psi[CH2NH2+], and psi[(E)-CH=CH] isosteres. Ala-Gly isostere building blocks were then synthesized and introduced in CII260-267 and CII259-273 glycopeptides. The modified glycopeptides were evaluated for binding to the A(q) molecule, and the results were interpreted in view of the A(q)/glycopeptide model. Moreover, recognition by a panel of T-cell hybridomas revealed high sensitivity for the backbone modifications. These studies contribute to the understanding of the interactions in the ternary A(q)/glycopeptide/T-cell receptor complexes that activate T cells in autoimmune arthritis and suggest possibilities for new vaccination approaches.
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| 6. |
- Andresen Bergström, Moa, 1978, et al.
(författare)
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Oximes: Metabolic Activation and Structure−Allergenic Activity Relationships
- 2008
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 51:8, s. 2541-2550
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Tidskriftsartikel (refereegranskat)abstract
- Metabolic activation of chemicals (prohaptens) in the skin can cause allergic contact dermatitis. We have explored structure−allergenic activity relationships for seven potential oxime prohaptens using the local lymph node assay and a GSH trapping screen with liver microsomes. The general structure−allergenic activity relationships found were that an α,β-unsaturation is necessary for an oxime to be a prohapten and that increased steric hindrance around this double bond leads to reduction in sensitizing capacity. We also found that sensitizing oximes can be distinguished in vitro from nonsensitizers by monitoring of mono-oxidized (+16 Da) GSH conjugates in the GSH trapping screen. However, care should be taken when interpreting data from GSH trapping screens, as nonsensitizers may also form GSH conjugates via alternative mechanisms. This investigation emphasizes the importance of considering cutaneous bioactivation in toxicity assessment of chemicals used in contact with the skin.
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| 7. |
- Bach, Anders, et al.
(författare)
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Modified peptides as potent inhibitors of the postsynaptic density-95/N-methyl-D-aspartate receptor interaction.
- 2008
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 51:20, s. 6450-9
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Tidskriftsartikel (refereegranskat)abstract
- The protein-protein interaction between the NMDA receptor and its intracellular scaffolding protein, PSD-95, is a potential target for treatment of ischemic brain diseases. An undecapeptide corresponding to the C-terminal of the NMDA was used as a template for finding lead candidates for the inhibition of the PSD-95/NMDA receptor interaction. Initially, truncation and alanine scan studies were carried out, which resulted in a pentapeptide with wild-type affinity, as examined in a fluorescence polarization assay. Further examination was performed by systematic substitutions with natural and unnatural amino acids, which disclosed a tripeptide with micromolar affinity and N-methylated tetrapeptides with improved affinities. Molecular modeling studies guided further N-terminal modifications and introduction of a range of N-terminal substitutions dramatically improved affinity. The best compound, N-cyclohexylethyl-ETAV (56), demonstrated up to 19-fold lower K i value ( K i = 0.94 and 0.45 microM against PDZ1 and PDZ2 of PSD-95, respectively) compared to wild-type values, providing the most potent inhibitors of this interaction reported so far. These novel and potent inhibitors provide an important basis for development of small molecule inhibitors of the PSD-95/NMDA receptor interaction.
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| 8. |
- Bergmann, Rikke, et al.
(författare)
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SHOP: Scaffold HOPping by GRID-Based Similarity Searches
- 2007
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 50:11, s. 2708-2717
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Tidskriftsartikel (refereegranskat)abstract
- A new GRID-based method for scaffold hopping (SHOP) is presented. In a fully automatic manner, scaffolds were identified in a database based on three types of 3D-descriptors. SHOP's ability to recover scaffolds was assessed and validated by searching a database spiked with fragments of known ligands of three different protein targets relevant for drug discovery using a rational approach based on statistical experimental design. Five out of eight and seven out of eight thrombin scaffolds and all seven HIV protease scaffolds were recovered within the top 10 and 31 out of 31 neuraminidase scaffolds were in the 31 top-ranked scaffolds. SHOP also identified new scaffolds with substantially different chemotypes from the queries. Docking analysis indicated that the new scaffolds would have similar binding modes to those of the respective query scaffolds observed in X-ray structures. The databases contained scaffolds from published combinatorial libraries to ensure that identified scaffolds could be feasibly synthesized.
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| 9. |
- Bergström, Christel, et al.
(författare)
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Poorly soluble marketed drugs display solvation limited solubility
- 2007
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 50:23, s. 5858-5862
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Tidskriftsartikel (refereegranskat)abstract
- We determined the intrinsic aqueous solubility of 15 poorly soluble drugs with solubilities ranging from 2.9 nM to 1.1 μM. We then analyzed the data from a physicochemical perspective, using experimentally determined solid-state properties and easily interpretable two-dimensional molecular descriptors, to better understand the factors underlying poor solubility. The analysis shows that poorly soluble drugs that have reached the market are solubility limited by solvation rather than by their solid state.
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| 10. |
- Brindell, Malgorzata, et al.
(författare)
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Light-Induced Anticancer Activity of [RuCl2(DMSO)4] Complexes
- 2005
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 1520-4804 .- 0022-2623. ; 48:23, s. 7298-7304
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Tidskriftsartikel (refereegranskat)abstract
- The cytotoxicity and photocytotoxicity of trans-[RuCl2(DMSO)4] and cis-[RuCl2(DMSO)4] complexes was tested in two melanoma cell lines, human (SK-MEL 188) and mouse (S91). The trans isomer was found to be more effective for cell growth inhibition than its cis analogue both in the presence and in the absence of illumination. However, the antiproliferative activity of both isomers was significantly enhanced after irradiation with UVA light in comparison with their activity observed in the dark. The influence of light on the reaction of both ruthenium(II) isomers with the single-stranded hexanucleotide d(T2GGT2), chosen as a model system for DNA, was also studied using chromatography and mass spectrometry techniques. The photochemical reaction of the ruthenium(II) complexes with the oligonucleotide d(T2GGT2) resulted in the formation of Ru(G-N7)2 adducts, which was not observed in the same time scale in thermal reactions. The initial short irradiation of the inert cis isomer was found to facilitate the covalent adduct formation with d(T2GGT2) in the secondary thermal reactions and with a rate comparable to that found for the trans isomer, which is ca. 5-10 times more reactive in the dark.
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| 11. |
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| 12. |
- Carlsson, Jens, et al.
(författare)
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Combining docking, molecular dynamics and the linear interaction energy method to predict binding modes and affinities for non-nucleoside inhibitors to HIV-1 reverse transcriptase
- 2008
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 51:9, s. 2648-56
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Tidskriftsartikel (refereegranskat)abstract
- Docking, scoring, molecular dynamics (MD), and the linear interaction energy (LIE) method are used here to predict binding modes and affinities for a set of 43 non-nucleoside inhibitors to HIV-1 reverse transcriptase. Starting from a crystallographic structure, the binding modes of 43 inhibitors are predicted using automated docking. The Goldscore scoring function and the LIE method are then used to determine the relative binding free energies for the inhibitors. The Goldscore scoring function does not reproduce the relative binding affinities for the inhibitors, while the standard parametrization of the LIE method reproduces the experimental binding free energies for 39 inhibitors with an R (2) = 0.70 and an unsigned average error of 0.8 kcal/mol. The present calculations provide a validation of the combination of docking, MD, and LIE as a powerful tool in structure-based drug design, and the methodology is easily scalable for attaining a higher throughput of compounds.
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| 13. |
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| 14. |
- Cisneros, Jose Antonio, et al.
(författare)
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Structure-activity relationship of a series of inhibitors of monoacylglycerol hydrolysis-comparison with effects upon fatty acid amide hydrolase
- 2007
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Ingår i: Journal of Medicinal Chemistry. - Washington : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 50:20, s. 5012-5023
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Tidskriftsartikel (refereegranskat)abstract
- A series of 32 heterocyclic analogues based on the structure of 2-arachidonoylglycerol (2-AG) were synthesized and tested for their ability to inhibit monoacylglycerol lipase and fatty acid an-tide hydrolase activities. The designed compounds feature a hydrophobic moiety and different heterocyclic subunits that mimic the glycerol fragment. This series has allowed us to carry out the first systematic structure activity relationship study on inhibition of 2-AG hydrolysis. The most promising compounds were oxiran-2-ylmethyl (5Z,8Z,l 11Z,14Z)-icosa-5,8,11,14-tetraenoate (1) and tetrahydro-2H-pyran-2-ylmethyl (5Z,8Z,11Z,14z)-icosa5,8,11,14-tetraenoate (5). They inhibited cytosolic 2-oleoylglycerol (2-OG) hydrolysis completely (IC50 values of 4.5 and 5.6 mu M, respectively). They also blocked, albeit less potently, 2-OG hydrolysis in membrane fractions (IC50 values of 19 and 26,mu M, respectively) and anandamide hydrolysis (IC50 values of 12 and 51 mu M, respectively). These compounds will be useful in delineating the importance of the cytosolic hydrolytic activity in the regulation of 2-AG levels and, hence, its potential as a target for drug development.
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| 15. |
- Dahlgren, Markus, et al.
(författare)
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Design, Synthesis, and Multivariate Quantitative Structure-Activity Relationship of Salicylanilides-Potent Inhibitors of Type III Secretion in Yersinia
- 2007
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 50:24, s. 6177-6188
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Tidskriftsartikel (refereegranskat)abstract
- Analogues to the salicylanilide N-(4-Chlorophenyl)-2-acetoxy-3,5-diiodobenzamide, 1a, an inhibitor of type III secretion (T3S) in Yersinia, were selected, synthesized, and biologically evaluated in three cycles. First, a set of analogues with variations in the salicylic acid ring moiety was synthesized to probe possible structural variation. A basic structure-activity relationship was established and then used to cherry-pick compounds from a principal component analysis score plot of salicylanilides to generate a second set. A third set with increased likelihood of biological activity was designed using D-optimal onion design. A quantitative structure-activity relationship model using hierarchical partial least-square regression to latent structures (Hi-PLS) was computed using PLS score vectors of building blocks correlated to the % inhibition of T3S as a response. A PLS discriminant analysis (PLS-DA) model was derived using the same descriptor set as that for the Hi-PLS model. Both models were validated with an external test set.
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| 16. |
- Delaine, Tamara, et al.
(författare)
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Galectin-inhibitory thiodigalactoside ester derivatives have antimigratory effects in cultured lung and prostate cancer cells.
- 2008
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 1520-4804 .- 0022-2623. ; 51:24, s. 8109-8114
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Tidskriftsartikel (refereegranskat)abstract
- Aromatic 3,3'-diesters of thiodigalactoside were synthesized in a rapid three-step sequence from commercially available thiodigalactoside and evaluated as inhibitors of cancer- and immunity-related galectins. For each of galectins-1, -3, -7, and -9N-terminal domain, aromatic 3,3'-diesters of thiodigalactoside were found to have affinities in the low micromolar range, which represents a 7-70 fold enhancement over thiodigalactoside itself. No significant improvement was found for galectin-8 N-terminal domain. Two of the compounds were selected for testing in cell culture and were shown to have potent antimigratory effects on human PC-3 prostate and human A549 nonsmall-cell lung cancer cells.
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| 17. |
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| 18. |
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| 19. |
- Ekegren, Jenny K, et al.
(författare)
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A new class of HIV-1 protease inhibitors containing a tertiary alcohol in the transition-state mimicking scaffold
- 2005
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 48:25, s. 8098-8102
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Tidskriftsartikel (refereegranskat)abstract
- Novel HIV-1 protease inhibitors encompassing a tertiary alcohol as part of the transition-state mimicking unit have been synthesized. Variation of the P1‘−P3‘ residues and alteration of the tertiary alcohol absolute stereochemistry afforded 10 inhibitors. High potencies for the compounds with (S)-configuration at the carbon carrying the tertiary hydroxyl group were achieved with Ki values down to 2.4 nM. X-ray crystallographic data for a representative compound in complex with HIV-1 protease are presented.
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| 20. |
- Ekegren, Jenny K, et al.
(författare)
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Microwave-accelerated synthesis of P1'-extended HIV-1 protease inhibitors encompassing a tertiary alcohol in the transition-state mimicking scaffold
- 2006
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 49:5, s. 1828-1832
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Tidskriftsartikel (refereegranskat)abstract
- Two series of P1'-extended HIV-1 protease inhibitors comprising a tertiary alcohol in the transition-state mimic exhibiting Ki values ranging from 2.1 to 93 nM have been synthesized. Microwave-accelerated palladium-catalyzed cross-couplings were utilized to rapidly optimize the P1' side chain. High cellular antiviral potencies were encountered when the P1' benzyl group was elongated with a 3- or 4-pyridyl substituent (EC50 = 0.18-0.22 microM). X-ray crystallographic data were obtained for three inhibitors cocrystallized with the enzyme.
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| 21. |
- Ellis, Gemma L, et al.
(författare)
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Two-Step synthesis of Achiral Dispiro-1,2,4,5-tetraoxanes with outstanding antimalarial activity, low toxicity, and high-stability profiles
- 2008
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 51:7, s. 2170-2177
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Tidskriftsartikel (refereegranskat)abstract
- A rapid, two step synthesis of a range of dispiro-1,2,4,5-tetraoxanes with potent antimalarial activity both in vitro and in vivo has been achieved. These 1,2,4,5-tetraoxanes have been proven to be superior to 1,2,4-trioxolanes in terms of stability and to be superior to trioxane analogues in terms of both stability and activity. Selected analogues have in vitro nanomolar antimalarial activity, good oral activity and are non-toxic in screens for both cytotoxicity and genotoxicity. The synthesis of a fluorescent NBD-tagged tetraoxane probe has allowed investigation into the mechanism of accumulation of these drugs using laser scanning confocal microscopy techniques.
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| 22. |
- Erdelyi, Mate, 1975, et al.
(författare)
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The Conformational Preferences of Natural and C3-Modified Epothilones in Aqueous Solution
- 2008
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Ingår i: J. Med. Chem.. - : American Chemical Society (ACS). ; 51:5, s. 1469-73
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Tidskriftsartikel (refereegranskat)abstract
- The conformational properties of the microtubule-stabilizing agent epothilone A (1a) and its 3-deoxy and 3-deoxy-2,3-didehydro derivatives 2 and 3 have been investigated in aqueous solution by a combination of NMR spectroscopic methods, Monte Carlo conformational searches, and NAMFIS calculations. The tubulinbound conformation of epothilone A (1a), as previously proposed on the basis of solution NMR data, was found to represent a significant fraction of the ensemble of conformations present for the free ligands in aqueous solution.
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| 23. |
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| 24. |
- Fridén, Markus, et al.
(författare)
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Structure-brain exposure relationships in rat and human using a novel data set of unbound drug concentrations in brain interstitial and cerebrospinal fluids
- 2009
-
Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 52:20, s. 6233-6243
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Tidskriftsartikel (refereegranskat)abstract
- New experimental methodologies were applied to measure the unbound brain-to-plasma concentration ratio (K(p,uu,brain)) and the unbound CSF-to-plasma concentration ratio (K(p,uu,CSF)) in rats for 43 structurally diverse drugs. The relationship between chemical structure and K(p,uu,brain) was dominated by hydrogen bonding. Contrary to popular understanding based on the total brain-to-plasma concentration ratio (logBB), lipophilicity was not a determinant of unbound brain exposure. Although changing the number of hydrogen bond acceptors is a useful design strategy for optimizing K(p,uu,brain), future improvement of in silico prediction models is dependent on the accommodation of active drug transport. The structure-brain exposure relationships found in the rat also hold for humans, since the rank order of the drugs was similar for human and rat K(p,uu,CSF). This cross-species comparison was supported by K(p,uu,CSF) being within 3-fold of K(p,uu,brain) in the rat for 33 of 39 drugs. It was, however, also observed that K(p,uu,CSF) overpredicts K(p,uu,brain) for highly effluxed drugs, indicating lower efflux capacity of the blood-cerebrospinal fluid barrier compared to the blood-brain barrier.
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| 25. |
- Gardner, Richard Andrew, et al.
(författare)
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Synthesis and transfection efficiencies of new lipophilic polyamines
- 2007
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 1520-4804 .- 0022-2623. ; 50:2, s. 308-318
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Tidskriftsartikel (refereegranskat)abstract
- A homologous series of lipophilic polyamines was synthesized and evaluated for DNA delivery and transfection efficiency. The series contained 1,4-butanediamine, 1,8-octanediamine, 2-[2-(2-amino-ethoxy)-ethoxy]-ethylamine, homospermidine, and homospermine covalently attached via their N-1 terminus to a 3,4-bis(oleyloxy)-benzyl motif. In addition, homospermidine and homospermine were also attached via amide linkers. The homospermidine derivatives (i.e., benzyl tether 25 and benzamide tether 27) showed a 3-fold and 4-fold respective enhancement in delivery of AlexaFluor-488-labeled DNA over the butanediamine analogue 22. Homospermine derivative 26 was shown to inhibit C-14-spermine uptake (IC50 similar to 10 mu M), which implied that 26 is able to compete effectively for polyamine recognition sites on the cell surface. This study demonstrated that the number and position of the positive charges along the polyamine scaffold plays a key role in DNA delivery and in determining the transfection efficiency.
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| 26. |
- Geitmann, Matthis, et al.
(författare)
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Biosensor-based kinetic characterization of the interaction between HIV-1 reverse transcriptase and non-nucleoside inhibitors
- 2006
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 49:8, s. 2367-74
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Tidskriftsartikel (refereegranskat)abstract
- Details of the interaction between HIV-1 reverse transcriptase and non-nucleoside inhibitors (NNRTIs) have been elucidated using a biosensor-based approach. This initial study was performed with HIV-1 reverse transcriptase mutant K103N, the phenethylthioazolylthiourea compound (PETT) MIV-150, and the three NNRTIs licensed for clinical use: nevirapine, delavirdine, and efavirenz. Mathematical evaluation of the experimental data with several interaction models revealed that the four inhibitors interacted with HIV-1 RT with varying degrees of complexity. The simplest adequate model accounted for two different conformations of the free enzyme, of which only one can bind the inhibitor, consistent with a previously hypothesized population-shift model including a preformation of the NNRTI binding site. In addition, a heterogeneous binding was observed for delavirdine, efavirenz, and MIV-150, indicating that two noncompetitive and kinetically distinct enzyme-inhibitor complexes could be formed. Furthermore, for these compounds, there were indications for ligand-induced conformational changes.
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| 27. |
- Geitmann, Matthis, et al.
(författare)
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Interaction kinetic characterization of HIV-1 reverse transcriptase non-nucleoside inhibitor resistance
- 2006
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 49:8, s. 2375-87
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Tidskriftsartikel (refereegranskat)abstract
- To decipher the mechanism for non-nucleoside inhibitor resistance of HIV-1 reverse transcriptase, the kinetics of the interaction between wild type and drug-resistant variants of the enzyme and structurally diverse inhibitors were determined. Substitution of amino acid residues in the inhibitor binding site resulted in altered rate constants for the pre-equilibrium between two unliganded forms of the enzyme, and for the association and dissociation of the inhibitor-enzyme interaction. The Y181C, V108I, and P225H substitutions affected primarily the association and dissociation rate constants, while the K103N and the L100I substitutions also influenced the equilibrium between the two forms of the free enzyme. The K103N and the L100I substitutions were found to facilitate both the entry of the inhibitor into the binding pocket as well as its exit, in contrast to what has been reported elsewhere. Interaction kinetic-based resistance profiles showed that phenethylthiazolylthiourea compounds were relatively insensitive to the studied substitutions.
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| 28. |
- Georgsson, Jennie, et al.
(författare)
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Angiotensin II Pseudopeptides Containing 1,3,5-Trisubstituted Benzene Scaffolds with High AT2 Receptor Affinity
- 2005
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 48:21, s. 6620-6631
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Tidskriftsartikel (refereegranskat)abstract
- Two 1,3,5-trisubstituted aromatic scaffolds intended to serve as γ-turn mimetics have been synthesized and incorporated in five pseudopeptide analogues of angiotensin II (Asp-Arg-Val-Tyr-Ile-His-Pro-Phe), replacing Val-Tyr-Ile, Val-Tyr, or Tyr-Ile. All the tested compounds exhibited nanomolar affinity for the AT2 receptor with the best compound (3) having a Ki of 1.85 nM. Four pseudopeptides were AT2 selective, while one (5) also exhibited good affinity for the AT1 receptor (Ki = 30.3 nM). This pseudopeptide exerted full agonistic activity in an AT2 receptor induced neurite outgrowth assay but displayed no agonistic effect in an AT1 receptor functional assay. Molecular modeling, using the program DISCOtech, showed that the high-affinity ligands could interact similarly with the AT2 receptor as other ligands with high affinity for this receptor. A tentative agonist model is proposed for AT2 receptor activation by angiotensin II analogues. We conclude that the 1,3,5-trisubstituted benzene rings can be conveniently prepared and are suitable as γ-turn mimics.
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| 29. |
- Georgsson, Jennie, et al.
(författare)
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Synthesis of a new class of druglike angiotensin II C-terminal mimics with affinity for the AT2 receptor
- 2007
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 50:7, s. 1711-1715
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Tidskriftsartikel (refereegranskat)abstract
- Four tripeptides corresponding to the C-terminal region of angiotensin II were synthesized. One of these peptides (Ac-His-Pro-Ile) showed moderate binding affinity for the AT2 receptor. Two aromatic histidine-related scaffolds were synthesized and introduced in the tripeptides to give eight new peptidomimetic structures. Three of the new peptide-derived druglike molecules exhibited selective, nanomolar affinity for the AT2 receptor. These ligands may become lead compounds in the future development of novel classes of selective AT2 receptor agonists.
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| 30. |
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| 31. |
- Hill, Timothy A, et al.
(författare)
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Inhibition of dynamin mediated endocytosis by the dynoles : synthesis and functional activity of a family of indoles
- 2009
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 52:12, s. 3762-3773
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Tidskriftsartikel (refereegranskat)abstract
- Screening identified two bisindolylmaleimides as 100 microM inhibitors of the GTPase activity of dynamin I. Focused library approaches allowed development of indole-based dynamin inhibitors called dynoles. 100-Fold in vitro enhancement of potency was noted with the best inhibitor, 2-cyano-3-(1-(2-(dimethylamino)ethyl)-1H-indol-3-yl)-N-octylacrylamide (dynole 34-2), a 1.3 +/- 0.3 microM dynamin I inhibitor. Dynole 34-2 potently inhibited receptor mediated endocytosis (RME) internalization of Texas red-transferrin. The rank order of potency for a variety of dynole analogues on RME in U2OS cells matched their rank order for dynamin inhibition, suggesting that the mechanism of inhibition is via dynamin. Dynoles are the most active dynamin I inhibitors reported for in vitro or RME evaluations. Dynole 34-2 is 15-fold more active than dynasore against dynamin I and 6-fold more active against dynamin mediated RME (IC(50) approximately 15 microM; RME IC(50) approximately 80 microM). The dynoles represent a new series of tools to better probe endocytosis and dynamin-mediated trafficking events in a variety of cells.
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| 32. |
- Hill, Timothy, et al.
(författare)
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Small molecule inhibitors of dynamin I GTPase activity : development of dimeric tyrphostins.
- 2005
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 48:24
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Tidskriftsartikel (refereegranskat)abstract
- Dynamin I is a GTPase enzyme required for endocytosis and is an excellent target for the design of potential endocytosis inhibitors. Screening of a library of tyrphostins, in our laboratory, against the GTPase activity of dynamin I gave rise to a microM potent lead, 2-cyano-3-(3,4-dihydroxyphenyl)thioacrylamide (1, IC50 70 microM). Our initial investigations suggested that only the dimeric form of 1 displayed dynamin I GTPase inhibitory activity. Subsequent synthetic iterations were based on dimeric analogues and afforded a number of small molecules, low microM potent, inhibitors of dynamin I GTPase, in particular, symmetrical analogues with a minimum of two free phenolic -OHs: catechol-acrylamide (9) (IC50= 5.1 +/- 0.6 microM), its 3,4,5-trihydroxy congener (10) (IC50= 1.7 +/- 0.2 microM), and the corresponding 3-methyl ether (11) (IC50= 9 +/- 3 microM). Increasing the length of the central alkyl spacer from ethyl to propyl (22-24) afforded essentially identical activity with IC50's of 1.7 +/- 0.2, 1.7 +/- 0.2, and 5 +/- 1 microM, respectively. No decrease in activity was noted until the introduction of a hexyl spacer. Our studies highlight the requirement for two free amido NHs with neither the mono-N-methyl (86) nor the bis-N-methyl (87) analogues inhibiting dynamin I GTPase. A similar effect was noted for the removal of the nitrile moieties. However, modest potency was observed with the corresponding ester analogues of 9-11: ethyl ester (90), propyl ester (91), and butyl ester (92), with IC50's of 42 +/- 3, 38 +/- 2, and 61 +/- 2 microM, respectively. Our studies reveal the most potent and promising dynamin I GTPase inhibitor in this series as (22), which is also known as BisT.
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| 33. |
- Holm, Lotta, et al.
(författare)
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Quantitative Structure-Activity Relationship of Peptides Binding to the Class II Major Histocompatibility Complex Molecule A(q) Associated with Autoimmune Arthritis.
- 2007
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 1520-4804 .- 0022-2623. ; 50:9, s. 2049-2059
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Tidskriftsartikel (refereegranskat)abstract
- Presentation of (glyco)peptides by the class II major histocompatibility complex molecule Aq to T cells plays a central role in collagen-induced arthritis, an animal model for the autoimmune disease rheumatoid arthritis. A peptide library was designed using statistical molecular design in amino acid space in which five positions in the minimal mouse collagen type II binding epitope CII260-267 were varied. A substantially reduced peptide library of 24 peptides with diverse and representative molecular characteristics was selected, synthesized, and evaluated for the binding strength to Aq. A multivariate QSAR model was established by correlating calculated descriptors, compressed to its principle properties, with the binding data using partial least-square regression. The model was successfully validated by an external test set. Interpretation of the model provided a molecular property binding motif for peptides interacting with Aq. The information may be useful in future research directed toward new treatments of rheumatoid arthritis.
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| 34. |
- Hu, Baihua, et al.
(författare)
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Discovery of phenyl acetic acid substituted quinolines as novel liver X receptor agonists for the treatment of atherosclerosis
- 2006
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 49:21, s. 6151-6154
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Tidskriftsartikel (refereegranskat)abstract
- A structure-based approach was used to optimize our new class of quinoline LXR modulators leading to phenyl acetic acid substituted quinolines 15 and 16. Both compounds displayed good binding affinity for LXRâ and LXRR and were potent activators in LBD transactivation assays. The compounds also increased expression of ABCA1 and stimulated cholesterol efflux in THP-1 cells. Quinoline 16 showed good oral bioavailability and in vivo efficacy in a LDLr knockout mouse model for lesions.
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| 35. |
- Hubatsch, Ina, et al.
(författare)
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Beta- and gamma-di- and tripeptides as potential substrates for the oligopeptide transporter hPepT1
- 2007
-
Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 50:21, s. 5238-5242
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Tidskriftsartikel (refereegranskat)abstract
- The hPepT1-mediated transport properties of a series of 11 synthesized beta- and gamma-peptides have been studied in Caco-2 cells. The results show that several of the compounds interact with the peptide transporter, but only two beta-dipeptides act as substrates and are transported across the cell monolayers. These two are less-efficient substrates than alfa-peptides. Larger derivatives than beta-dipeptides do not act as hPepT1 substrates, but instead, they appear to be substrates for P-glycoprotein efflux.
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| 36. |
- Jacobsson, Micael, et al.
(författare)
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Identification of Plasmodium falciparum spermidine synthase active site binders through structure-based virtual screening
- 2008
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 51:9, s. 2777-2786
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Tidskriftsartikel (refereegranskat)abstract
- Seven novel binders, binding in the active site of Plasmodium falciparum spermidine synthase, were identified by structure-based virtual screening. The binding of these compounds was experimentally verified by NMR techniques. Spermidine synthase, an enzyme involved in the polyamine pathway, has been suggested as a target for treating malaria. The virtual screening protocol combined 3D pharmacophore filtering, docking, and scoring, focusing on finding compounds predicted to form interactions mimicking those of a previously known binder. The virtual screen resulted in the selection of 28 compounds that were acquired and tested from 2.6 million starting structures. Two of the seven binders were predicted to bind in the amino substrate binding pocket. Both of these showed stronger binding upon addition of methylthioadenosine, one of the two products of the enzyme, and a known binder and inhibitor. The five other compounds were predicted to bind in the part of the active site where the other substrate, decarboxylated S-adenosylmethionine, binds. These five compounds all competed for binding with methylthioadenosine.
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| 37. |
- Jacobsson, Mårten, et al.
(författare)
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Selective antiproliferative activity of hydroxynaphthyl-beta-D-xylosides
- 2006
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 1520-4804 .- 0022-2623. ; 49:6, s. 1932-1938
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Tidskriftsartikel (refereegranskat)abstract
- The antiproliferative activity of the 14 isomeric monoxylosylated dihydroxynaphthalenes has been tested in vitro toward normal HFL-1 and 3T3 A31 cells as well as transformed T24 and 3T3 SV40 cells. The antiproliferative effect toward HFL-1 cells was correlated with the polarity of the compounds. However, in the case of transformed T24 cells, some compounds showed a clearly different behavior resulting in a selective antiproliferative effect. No such correlation was found for normal 3T3 A31 or virus transformed 3T3 SV40 cells, nor for the free aglycon. These results suggest that the antiproliferative activity shown by naphthoxylosides is diverse in different cell lines and dependent on the nature of the aglycon. The anti proliferative effect of 2- (6-hydroxynaphthyl)-beta-D-xylopyranoside, in contrast to inactive 2-naphthyl-beta-D-xylopyranoside, on T24 cells was accompanied by increased apoptosis as indicated by a TUNEL assay.
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| 38. |
- Johansson, Per-Ola, et al.
(författare)
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Design and synthesis of potent inhibitors of plasmepsin I and II : x-ray crystal structure of inhibitor in complex with plasmepsin II
- 2005
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 48:13, s. 4400-4409
-
Tidskriftsartikel (refereegranskat)abstract
- New and potent inhibitors of the malarial aspartic proteases plasmepsin (Plm) I and II, from the deadliest malaria parasite Plasmodium falciparum, have been synthesized utilizing Suzuki coupling reactions on previously synthesized bromobenzyloxy-substituted statine-like inhibitors. The enzyme inhibition activity has been improved up to eight times by identifying P1 substituents that effectively bind to the continuous S1-S3 crevice of Plasmepsin I and II. By replacement of the bromo atom in the P1 p-bromobenzyloxy-substituted inhibitors with different aryl substituents, several inhibitors exhibiting Ki values in the low nanomolar range for both Plm I and II have been identified. Some of these inhibitors are also effective in attenuating parasite growth in red blood cells, with the best inhibitors, compounds 2 and 4, displaying 70% and 83% inhibition, respectively, at a concentration of 5 μM. The design was partially guided by the X-ray crystal structure disclosed herein of the previously synthesized inhibitor 1 in complex with plasmepsin II. © 2005 American Chemical Society.
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| 39. |
- Johansson, Susanne, et al.
(författare)
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Design, synthesis, and evaluation of N-acyl modified sialic acids as inhibitors of adenoviruses causing epidemic keratoconjunctivitis
- 2009
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 52:12, s. 3666-3678
-
Tidskriftsartikel (refereegranskat)abstract
- The adenovirus serotype Ad37 binds to and infects human corneal epithelial (HCE) cells through attachment to cellular glycoproteins carrying terminal sialic acids. By use of the crystallographic structure of the sialic acid-interacting domain of the Ad37 fiber protein in complex with sialyllactose, a set of N-acyl modified sialic acids were designed to improve binding affinity through increased hydrophobic interactions. These N-acyl modified sialic acids and their corresponding multivalent human serum albumin (HSA) conjugates were synthesized and tested in Ad37 cell binding and cell infectivity assays. Compounds bearing small substituents were as effective inhibitors as sialic acid. X-ray crystallography and overlays with the Ad37-sialyllactose complex showed that the N-acyl modified sialic acids were positioned in the same orientation as sialic acid. Their multivalent counterparts achieved a strong multivalency effect and were more effective to prevent infection than the monomers. Unfortunately, they were less active as inhibitors than multivalent sialic acid.
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| 40. |
- Karoli, Tomislav, et al.
(författare)
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Synthesis, biological activity, and preliminary pharmacokinetic evaluation of analogues of a phosphosulfomannan angiogenesis inhibitor (PI-88).
- 2005
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Ingår i: Journal of medicinal chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 48:26, s. 8229-36
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Tidskriftsartikel (refereegranskat)abstract
- The phosphosulfomannan 1 (PI-88) is a mixture of highly sulfated oligosaccharides that is currently undergoing clinical evaluation in cancer patients. As well as its anticancer properties, 1 displays a number of other interesting biological activities. A series of analogues of 1 were synthesized with a single carbon (pentasaccharide) backbone to facilitate structural characterization and interpretation of biological results. In a fashion similar to 1, all compounds were able to inhibit heparanase and to bind tightly to the proangiogenic growth factors FGF-1, FGF-2, and VEGF. The compounds also inhibited the infection of cells and cell-to-cell spread of herpes simplex virus (HSV-1). Preliminary pharmacokinetic data indicated that the compounds displayed different pharmacokinetic behavior compared with 1. Of particular note was the n-octyl derivative, which was cleared 3 times less rapidly than 1 and may provide increased systemic exposure.
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| 41. |
- Lager, Erik, et al.
(författare)
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4-quinolone derivatives: High-affinity ligands at the benzodiazepine site of brain GABA(A) receptors. synthesis, pharmacology, and pharmacophore modeling
- 2006
-
Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 1520-4804 .- 0022-2623. ; 49:8, s. 2526-2533
-
Tidskriftsartikel (refereegranskat)abstract
- The 3-ethoxycarbonyl-4-quinolone compound I has previously been identified via a database search as an interesting lead compound for ligand binding at the benzodiazepine site of GABA(A) receptors (Kahnberg et al. J. Mol. Graphics Modelling 2004, 23, 253-261). Pharmacophore-guided optimization of this lead compound yielded a number of high-affinity ligands for the benzodiazepine site including compounds 20 and 23-25 displaying sub-nanomolar affinities. A few of the compounds have been tested on the alpha(1)beta(2)gamma(2s) and alpha(3)beta(2)gamma(2s) GABA(A) receptor subtypes, and two of the compounds (5 and 19) display selectivity for alpha(1) versus alpha(3)-containing receptors by a factor of 22 and 27, respectively. This selectivity for alpha(1)beta(2)gamma(2s) is in the same range as that for the well-known alpha(1) subunit selective compound zolpidem.
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| 42. |
- Larsson, Anders, et al.
(författare)
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Identification of the brominated flame retardant 1,2-dibromo-4-(1,2-dibromoethyl)cyclohexane as an androgen agonist
- 2006
-
Ingår i: Journal of medicinal chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 49:25, s. 7366-7372
-
Tidskriftsartikel (refereegranskat)abstract
- To investigate androgen receptor (AR) activation by exogenous compounds, we used a combination of experimental analysis and theoretical modeling to compare a set of brominated flame retardants (BFRs) to dihydrotestosterone (DHT) with regard to ligand docking, AR binding, and AR activation in human hepatocellular liver carcinoma cells, as well as interacting energy analysis. Modeling of receptor docking was found to be a useful first step in predicting the potential to translocate to the ligand pocket of the receptor, and the computed interaction energy was found to correlate with the observed binding affinity. Flexible alignment studies of the BFR compounds demonstrated that 1,2-dibromo-4-(1,2-dibromoethyl)cyclohexane (BCH) closely overlap DHT. Combining the theoretical modeling with in vitro ligand-binding and receptor-activation assays, we show that BCH binds to and activates the human AR. The remaining BFRs did not successfully interact with the ligand pocket, were not able to replace a synthetic androgen from the receptor, and failed to activate the receptor.
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| 43. |
- Larsson, Andreas, et al.
(författare)
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Multivariate design, synthesis, and biological evaluation of peptide inhibitors of FimC/FimH protein-protein interactions in uropathogenic Escherichia coli
- 2005
-
Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 48:4, s. 935-945
-
Tidskriftsartikel (refereegranskat)abstract
- A peptide library targeting protein-protein interactions crucial for pilus assembly in Gram negative bacteria has been designed using statistical molecular design. A nonamer peptide scaffold was used, with seven positions being varied. The selection was performed in the building block space, and previously known structure-activity data were included in the design procedure. This resulted in a heavily reduced library consisting of 32 peptides which was prepared by solid-phase synthesis. The ability of the peptides to inhibit the protein-protein interaction between the periplasmic chaperone FimC and the pilus adhesin FimH was then determined in an ELISA. Novel peptides with the capability to inhibit the FimC/FimH protein(-)protein interaction to the same extent as the native FimC peptides were discovered. Multivariate QSAR studies of the response in the ELISA gave valuable information on the properties of amino acids which were preferred at the seven positions in the nonamer scaffold. This information can be used in attempts to develop optimized peptides and peptidomimetics that inhibit pilus assembly in pathogenic bacteria.
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| 44. |
- Lehmann, Fredrik, 1976, et al.
(författare)
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Novel potent and efficacious nonpeptidic urotensin II receptor agonists
- 2006
-
Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 49, s. 2232-2240
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Tidskriftsartikel (refereegranskat)abstract
- Six different series of nonpeptidic urotensin II receptor agonists have been synthesized and evaluated for their agonistic activity in a cell-based assay (R-SAT). The compounds are ring-opened analogues of the isochromanone-based agonist AC-7954 with different functionalities constituting the linker between the two aromatic ring moieties. Several of the compounds are highly potent and efficacious, with N-[1-(4-chlorophenyl)-3-(dimethylamino)- propyl]-4-phenylbenzamide oxalate (5d) being the most potent. The pure enantiomers of 5d were obtained from the corresponding diastereomeric amides. It was shown by a combination of X-ray crystallography and chemical correlation that the activity resides in the S-enantiomer of 5d (pEC50 7.49). © 2006 American Chemical Society.
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| 45. |
- Lehtiö, Lari, et al.
(författare)
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Structural basis for inhibitor specificity in human poly(ADP-ribose) polymerase-3.
- 2009
-
Ingår i: Journal of medicinal chemistry. - : American Chemical Society (ACS). - 1520-4804 .- 0022-2623. ; 52:9, s. 3108-11
-
Tidskriftsartikel (refereegranskat)abstract
- Poly(ADP-ribose) polymerases (PARPs) activate DNA repair mechanisms upon stress- and cytotoxin-induced DNA damage, and inhibition of PARP activity is a lead in cancer drug therapy. We present a structural and functional analysis of the PARP domain of human PARP-3 in complex with several inhibitors. Of these, KU0058948 is the strongest inhibitor of PARP-3 activity. The presented crystal structures highlight key features for potent inhibitor binding and suggest routes for creating isoenzyme-specific PARP inhibitors.
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| 46. |
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| 47. |
- Musa, Klefah A K, et al.
(författare)
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Mechanism of Photoinduced Decomposition of Ketoprofen
- 2007
-
Ingår i: Journal of Medicinal Chemistry. - Washington, DC : American Chemical Society. - 0022-2623 .- 1520-4804. ; 50:8, s. 1735-1743
-
Tidskriftsartikel (refereegranskat)abstract
- UV-induced decarboxylation of the NSAID ketoprofen, followed by activation of molecular oxygen or formation of a decarboxylated peroxide adduct, is explored using computational quantum chemistry. The excited energy surfaces reveal that the neutral species will not decarboxylate, whereas the deprotonated acid decarboxylates spontaneously in the triplet state, and with an associated 3-5 kcal/mol barrier from several low-lying excited singlet states. The observed long lifetimes of the decarboxylated anion is explained in terms of the high stability of the triplet benzoyl ethyl species with protonated carbonylic oxygen, from which there is no obvious decay channel. Mechanisms for the generation of singlet oxygen and superoxide are discussed in detail. Addition of molecular oxygen to give the corresponding peroxyl radical capable of initiating propagating lipid peroxidation reactions is also explored. The computed data explains all features of the observed experimental observations made to date on the photodegradation of ketoprofen.
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| 48. |
- Nerelius, Charlotte, et al.
(författare)
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Poly-N-methylated Amyloid beta-Peptide (A beta) C-Terminal Fragments Reduce A beta Toxicity in Vitro and in Drosophila melanogaster
- 2009
-
Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 52, s. 8002-8009
-
Tidskriftsartikel (refereegranskat)abstract
- Alzheimer's disease (AD), an age related neurodegenerative disorder, threatens to become a major health-economic problem. Assembly of 40- or 42-residue amyloid beta-peptides (A beta) into neurotoxic oligo-/polymeric beta-sheet structures is an important pathogenic feature in AD, thus, inhibition of this process has been explored to prevent or treat AD. The C-terminal part plays an important role in A beta aggregation, but most A beta aggregation inhibitors have targeted the central region around residues 16-23. Herein, we synthesized hexapeptides with varying extents of N-methylation based on residues 32-37 of A beta to target its C-terminal region. We measured the peptides abilities to retard beta-sheet and fibril formation of A beta and to reduce A beta neurotoxicity. A penta-N-methylated peptide was more efficient than peptides with 0, 2, or 3 N-methyl groups. This penta-N-methylated peptide moreover increased life span and locomotor activity in Drosophila melanogaster flies overexpressing human A beta(1-42).
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| 49. |
- Nervall, Martin, et al.
(författare)
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Predicting Binding Modes from Free Energy Calculations
- 2008
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 51:9, s. 2657-2667
-
Tidskriftsartikel (refereegranskat)abstract
- To produce reliable predictions of bioactive conformations is a major challenge in the field of structurebased inhibitor design and is a requirement for accurate binding free energy predictions with structurebased methods. A series of HIV-1 reverse transcriptase inhibitors was cross-docked using a non-native crystal structure that resulted in two distinct clusters of possible conformations. One of these clusters was compatible with an existing crystal structure, whereas the other displayed a flipped heterocyclic group. Binding free energies, using the non-native crystal structure, calculated from several scoring functions, were similar for the two clusters, and no conclusion about the binding mode could be drawn from these results. The two clusters could be separated through rescoring with the linear interaction method (LIE) in combination with molecular dynamics simulations, which leads to a binding mode prediction in line with experimental crystallographic data. Further, the LIE model produces the best correlation between experimental and calculated binding free energies among the tested scoring methods.
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| 50. |
- Nordström, Helena, et al.
(författare)
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Identification of MMP-12 Inhibitors by Using Biosensor-Based Screening of a Fragment Library
- 2008
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 51:12, s. 3449-3459
-
Tidskriftsartikel (refereegranskat)abstract
- Small inhibitors of matrix metalloproteinase 12 (MMP-12) have been identified with a biosensor-based screening strategy and a specifically designed fragment library. The interaction between fragments and three variants of the target and a reference protein with an active-site zinc ion was measured continuously by surface plasmon resonance. The developed experimental design overcame the inherent instability of MMP-12 and allowed the identification of fragments that interacted specifically with the active-site of MMP-12 but not with the reference protein. The interaction with MMP-12 for selected compounds were analyzed for concentration dependence and saturability. Compounds interacting distinctly with the target were further evaluated by an activity-based assay, verifying MMP-12 inhibition. Two effective inhibitors were identified, and the compound with highest affinity was confirmed to be a competitive inhibitor with an IC50 of 290 nM and a ligand efficiency of 0.7 kcal/mol heavy atom. This procedure integrates selectivity and binding site identification into the screening procedure and does not require structure determination.
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