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Sökning: L773:1860 7179

  • Resultat 1-10 av 26
  • [1]23Nästa
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  • Borhade, Sanjay R., et al. (författare)
  • Preclinical Characterization of Acyl Sulfonimidamides : Potential Carboxylic Acid Bioisosteres with Tunable Properties
  • 2015
  • Ingår i: ChemMedChem. - 1860-7179 .- 1860-7187. ; 10:3, s. 455-460
  • Tidskriftsartikel (refereegranskat)abstract
    • Herein we present the preclinical characterization of novel compounds containing the linear acyl sulfonimidamide functionality. Specifically, we studied the pK(a), lipophilicity, in vitro metabolic stability, plasma protein binding, Caco-2 permeability, and aqueous solubility for nine aryl acyl sulfonimidamides. In comparison with widely used carboxylic acid bioisosteres, the acyl sulfonimidamides were found to be less acidic and more lipophilic depending on the substitution pattern in the studied compounds. Importantly, the pKa values (5.9-7.6) were significantly influenced by substituents on the nitrogen atom and the aryl substituents. Moreover, the acyl sulfonimidamides displayed membrane permeabilities ranging from moderate to very high, which correlated with decreased pKa and low to negligible efflux ratios. We foresee that the chiral sulfur center and the two handles for structural diversity of linear acyl sulfonimidamides will offer new opportunities for drug design and for improving the oral bioavailability of acidic drug candidates.
  • Briggner, Lars-Erik, et al. (författare)
  • In silico solid state perturbation for solubility improvement
  • 2014
  • Ingår i: ChemMedChem. - 1860-7179 .- 1860-7187. ; 9:4, s. 724-726
  • Tidskriftsartikel (refereegranskat)abstract
    • Solubility is a frequently recurring issue within pharmaceutical industry, and new methods to proactively resolve this are of fundamental importance. Here, a novel methodology is reported for intrinsic solubility improvement, using in silico prediction of crystal structures, by perturbing key interactions in the crystalline solid state. The methodology was evaluated with a set of benzodiazepine molecules, using the two‐dimensional molecular structure as the only a priori input. The overall trend in intrinsic solubility was correctly predicted for the entire set of benzodiazepines molecules. The results also indicate that, in drug compound series where the melting point is relatively high (i.e., “brick dust” compounds), the reported methodology should be very suitable for identifying strategically important molecular substitutions to improve solubility. As such, this approach could be a useful predictive tool for rational compound design in the early stages of drug development.
  • Di, Li, et al. (författare)
  • The Critical Role of Passive Permeability in Designing Successful Drugs
  • 2020
  • Ingår i: ChemMedChem. - 1860-7179 .- 1860-7187. ; 15:20, s. 1862-1874
  • Forskningsöversikt (refereegranskat)abstract
    • Passive permeability is a key property in drug disposition and delivery. It is critical for gastrointestinal absorption, brain penetration, renal reabsorption, defining clearance mechanisms and drug-drug interactions. Passive diffusion rate is translatable across tissues and animal species, while the extent of absorption is dependent on drug properties, as well as in vivo physiology/pathophysiology. Design principles have been developed to guide medicinal chemistry to enhance absorption, which combine the balance of aqueous solubility, permeability and the sometimes unfavorable compound characteristic demanded by the target. Permeability assays have been implemented that enable rapid development of structure-permeability relationships for absorption improvement. Future advances in assay development to reduce nonspecific binding and improve mass balance will enable more accurately measurement of passive permeability. Design principles that integrate potency, selectivity, passive permeability and other ADMET properties facilitate rapid advancement of successful drug candidates to patients.
  • Erdelyi, Mate, 1975, et al. (författare)
  • The Binding Mode of Side Chain- and C3-Modified Epothilones to Tubulin
  • 2010
  • Ingår i: ChemMedChem. - 1860-7179 .- 1860-7187. ; 5:6, s. 911-920
  • Tidskriftsartikel (refereegranskat)abstract
    • The tubulin-binding mode of C3- and C15-modified analogues of epothilone A (Epo A) was determined by NMR spectroscopy and computational methods and compared with the existing structural models of tubulin-bound natural Epo A. Only minor differences were observed in the conformation of the macrocycle between Epo A and the C3-modified analogues investigated. In particular, 3-deoxy- (compound 2) and 3-deoxy-2,3-didehydro-Epo A (3) were found to adopt similar conformations in the tubulin-binding cleft as Epo A, thus indicating that the 3-OH group is not essential for epothilones to assume their bioactive conformation. None of the available models of the tubulin-epothilone complex is able to fully recapitulate the differences in tubulin-polymerizing activity and microtubule-binding affinity between C20-modified epothilones 6 (C20-propyl), 7 (C20-butyl), and 8 (C20-hydroxypropyl). Based on the results of transferred NOE experiments in the presence of tubulin, the isomeric C15 quinoline-based Epo B analogues 4 and 5 show very similar orientations of the side chain, irrespective of the position of the nitrogen atom in the quinoline ring. The quinoline side chain stacks on the imidazole moiety of -His227 with equal efficiency in both cases, thus suggesting that the aromatic side chain moiety in epothilones contributes to tubulin binding through strong van der Waals interactions with the protein rather than hydrogen bonding involving the heteroaromatic nitrogen atom. These conclusions are in line with existing tubulin polymerization and microtubule-binding data for 4, 5, and Epo B.
  • Friedman, Ran, et al. (författare)
  • Discovery of plasmepsin inhibitors by fragment-based docking and consensus scoring
  • 2009
  • Ingår i: ChemMedChem. - 1860-7179 .- 1860-7187. ; 4:8, s. 1317-1326
  • Tidskriftsartikel (refereegranskat)abstract
    • Plasmepsins (PMs) are essential proteases of the plasmodia parasites and are therefore promising targets for developing drugs against malaria. We have discovered six inhibitors of PM II by high-throughput fragment-based docking of a diversity set of ∼40 000 molecules, and consensus scoring with force field energy functions. Using the common scaffold of the three most active inhibitors (IC50=2–5 μM), another seven inhibitors were identified by substructure search. Furthermore, these 13 inhibitors belong to at least three different classes of compounds. The in silico approach was very effective since a total of 13 active compounds were discovered by testing only 59 molecules in an enzymatic assay. This hit rate is about one to two orders of magnitude higher than those reported for medium- and high-throughput screening techniques in vitro. Interestingly, one of the inhibitors identified by docking was halofantrine, an antimalarial drug of unknown mechanism. Explicit water molecular dynamics simulations were used to discriminate between two putative binding modes of halofantrine in PM II.
  • Gaugaz, Fabienne Z, et al. (författare)
  • The impact of cyclopropane configuration on the biological activity of cyclopropyl-epothilones
  • 2014
  • Ingår i: ChemMedChem. - 1860-7179 .- 1860-7187. ; 9:10, s. 2227-2232
  • Tidskriftsartikel (refereegranskat)abstract
    • Two cis-12,13-cyclopropyl-epothilone B variants have been synthesized, differing only in the configuration of the stereocenters at C12 and C13. The syntheses were based on a common allylic alcohol intermediate that was converted into the corresponding diastereomeric hydroxymethyl-cyclopropanes by means of stereoselective Charette cyclopropanations. Macrocyclizations were accomplished through ring-closing metathesis (RCM). Substantial differences between the two compounds were found with regard to microtubule binding affinity, antiproliferative activity and their effects on the cellular microtubule network. While the analogue with the cyclopropane moiety oriented in a corresponding way to the epoxide configuration in natural epothilones was almost equipotent with epothilone A, the other was significantly less active. Based on these findings, natural epothilone-like activity of cis-fused 12,13-cyclopropyl-epothilone analogues is tightly linked to the natural orientation of the cyclopropane moiety.
  • Hartmann, Rafael, et al. (författare)
  • Rational Design of Azastatin as a Potential ADC Payload with Reduced Bystander Killing.
  • 2020
  • Ingår i: ChemMedChem. - 1860-7179 .- 1860-7187. ; 15:24, s. 2500-2512
  • Tidskriftsartikel (refereegranskat)abstract
    • Auristatins are a class of ultrapotent microtubule inhibitors, whose growing clinical popularity in oncology is based upon their use as payloads in antibody-drug conjugates (ADCs). The most widely utilized auristatin, MMAE, has however been shown to cause apoptosis in non-pathological cells proximal to the tumour ("bystander killing"). Herein, we introduce azastatins, a new class of auristatin derivatives encompassing a side chain amine for antibody conjugation. The synthesis of Cbz-azastatin methyl ester, which included the C2-elongation and diastereoselective reduction of two proteinogenic amino acids as key transformations, was accomplished in 22 steps and 0.76 % overall yield. While Cbz-protected azastatin methyl ester (0.13-3.0 nM) inhibited proliferation more potently than MMAE (0.47-6.5 nM), removal of the Cbz-group yielded dramatically increased IC50 -values (9.8-170 nM). We attribute the reduced apparent cytotoxicity of the deprotected azastatin methyl esters to a lack of membrane permeability. These results clearly establish the azastatins as a novel class of cytotoxic payloads ideally suited for use in next-generation ADC development.
  • Honarparvar, Bahareh, et al. (författare)
  • Pentacycloundecane-diol-Based HIV-1 Protease Inhibitors : Biological Screening, 2D NMR, and Molecular Simulation Studies
  • 2012
  • Ingår i: ChemMedChem. - 1860-7179 .- 1860-7187. ; 7:6, s. 1009-1019
  • Tidskriftsartikel (refereegranskat)abstract
    • Novel compounds incorporating a pentacycloundecane (PCU) diol moiety were designed, synthesized, and evaluated as inhibitors of the wild-type C-South African (C-SA) HIV-1 protease. Seven compounds are reported herein, three of which displayed IC50 values in the 0.50.6 mu M range. The cytotoxicity of PCU cage peptides toward human MT-4 cells appears to be several orders of magnitude less toxic than the current antiviral medications ritonavir and lopinavir. NMR studies based on the observed through-space 1H,1H distances/contacts in the EASY-ROESY spectra of three of the considered PCU peptide inhibitors enabled us to describe their secondary solution structure. Conserved hydrogen bonding interactions were observed between the hydroxy group of the PCU diol inhibitors and the catalytic triad (Asp25, Ile26, Gly27) of HIV protease in docking and molecular dynamics simulations. The biological significance and possible mode of inhibition by PCU-based HIV protease inhibitors discussed herein facilitates a deeper understanding of this family of inhibitors and their potential application to a vast number of alternative diseases related to proteases.
  • Horvath, Dragos, et al. (författare)
  • Design of a general-purpose European compound screening library for EU-OPENSCREEN
  • 2014
  • Ingår i: ChemMedChem. - 1860-7179 .- 1860-7187. ; 9:10, s. 2309-2326
  • Tidskriftsartikel (refereegranskat)abstract
    • This work describes a collaborative effort to define and apply a protocol for the rational selection of a general-purpose screening library, to be used by the screening platforms affiliated with the EU-OPENSCREEN initiative. It is designed as a standard source of compounds for primary screening against novel biological targets, at the request of research partners. Given the general nature of the potential applications of this compound collection, the focus of the selection strategy lies on ensuring chemical stability, absence of reactive compounds, screening-compliant physicochemical properties, loose compliance to drug-likeness criteria (as drug design is a major, but not exclusive application), and maximal diversity/coverage of chemical space, aimed at providing hits for a wide spectrum of drugable targets. Finally, practical availability/cost issues cannot be avoided. The main goal of this publication is to inform potential future users of this library about its conception, sources, and characteristics. The outline of the selection procedure, notably of the filtering rules designed by a large committee of European medicinal chemists and chemoinformaticians, may be of general methodological interest for the screening/medicinal chemistry community. The selection task of 200K molecules out of a pre-filtered set of 1.4M candidates was shared by five independent European research groups, each picking a subset of 40K compounds according to their own in-house methodology and expertise. An in-depth analysis of chemical space coverage of the library serves not only to characterize the collection, but also to compare the various chemoinformatics-driven selection procedures of maximal diversity sets. Compound selections contributed by various participating groups were mapped onto general-purpose self-organizing maps (SOMs) built on the basis of marketed drugs and bioactive reference molecules. In this way, the occupancy of chemical space by the EU-OPENSCREEN library could be directly compared with distributions of known bioactives of various classes. This mapping highlights the relevance of the selection and shows how the consensus reached by merging the five different 40K selections contributes to achieve this relevance. The approach also allows one to readily identify subsets of target-or target-class-oriented compounds from the EU-OPENSCREEN library to suit the needs of the diverse range of potential users. The final EU-OPENSCREEN library, assembled by merging five independent selections of 40K compounds from various expert groups, represents an excellent example of a Europe-wide collaborative effort toward the common objective of building best-in-class European open screening platforms.
  • Malo, Marcus, et al. (författare)
  • Investigation of D1 receptor-agonist interactions and D1/D2 agonist selectivity using a combination of pharmacophore and receptor homology modelling
  • 2012
  • Ingår i: ChemMedChem. - 1860-7179 .- 1860-7187. ; 7:3, s. 483-494
  • Tidskriftsartikel (refereegranskat)abstract
    • The aim of this study was to use a combined structure and pharmacophore modeling approach to extract information regarding dopamine D1 receptor agonism and D1/D2 agonist selectivity. A 3D structure model of the D1 receptor in its agonist-bound state was constructed with a full D1 agonist present in the binding site. Two different binding modes were identified using (+)-doxanthrine or SKF89626 in the modeling procedure. The 3D model was further compared with a selective D1 agonist pharmacophore model. The pharmacophore feature arrangement was found to be in good agreement with the binding site composition of the receptor model, but the excluded volumes did not fully reflect the shape of the agonist binding pocket. A new receptor-based pharmacophore model was developed with forbidden volumes centered on atom positions of amino acids in the binding site. The new pharmacophore model showed a similar ability to discriminate as the previous model. A comparison of the 3D structures and pharmacophore models of D1 and D2 receptors revealed differences in shape and ligand-interacting features that determine selectivity of D1 and D2 receptor agonists. A hydrogen bond pharmacophoric feature (Ser-TM5) was shown to contribute most to the selectivity. Non-conserved residues in the binding pocket that strongly contribute to D1/D2 receptor agonist selectivity were also identified; those were Ser/Cys3.36, Tyr/Phe5.38, Ser/Tyr5.41, and Asn/His6.55 in the transmembrane (TM) helix region, together with Ser/Ile and Leu/Asn in the second extracellular loop (EC2). This work provides useful information for the design of new selective D1 and D2 agonists. The combined receptor structure and pharmacophore modeling approach is considered to be general, and could therefore be applied to other ligand–protein interactions for which experimental information is limited.
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