| 1. |
- Ax, Anna, 1975-
(författare)
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Cyclic Sulfamide HIV-1 Protease Inhibitors : Design, Synthesis and Modelling
- 2005
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Ten years ago, the first protease inhibitor targeting the human immunodeficiency virus (HIV) was approved for clinical use. Highly active antiretroviral therapy (HAART), which combined protease and reverse transcriptase inhibitors, quickly became the standard therapy for treating patients infected with HIV and Acquired Immune Deficiency Syndrome (AIDS). Nevertheless, last year the AIDS pandemic reached its highest level ever. Many infected patients, mainly in the developing countries, are still without treatment. Among those patients who receive treatment, an increase in drug resistance and new-infection with drug-resistant strains are seen. To come to terms with these problems, new drugs that are efficient against resistant strains and can be produced at low cost are needed.In this study, we have focused our research efforts on cyclic sulfamides active as HIV-1 protease inhibitors. Distinctive to this compound class, as compared to the inhibitors so far approved for clinical use, was the incorporation of a water mimic that displaces the structural water (W301) observed in the X-ray crystal co-complexes. The first part of the study was aimed at understanding the rationale behind the nonsymmetric binding mode that the inhibitor adopted when bound to the enzyme. Symmetric and nonsymmetric inhibitors were synthesized and the structure-activity relationships and preferable binding modes were rationalized with the help of Comparative Molecular Field Analysis (CoMFA).In the second part of the study, an attempt was made to reduce the size of these inhibitors. As a result, the traditional P1/P1' substituents were removed, while the P2/P2' substituents were elongated in an attempt to reach between the binding sites. The design hypothesis was shown to be successful and inhibitors possessing nanomolar activity were identified.
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| 2. |
- Bengtsson, Marie, et al.
(författare)
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Structure-activity relationships for chain-shortened analogs of (Z)-5-decenyl acetate, a pheromone component of the turnip moth, Agrotis segetum
- 1990
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Ingår i: Journal of Chemical Ecology. - 0098-0331. ; 16:3, s. 667-684
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Tidskriftsartikel (refereegranskat)abstract
- Structure-activity relationships for chain-shortened analogs of (Z)-5-decenyl acetate, a pheromone component of the turnip moth, Agrotis segetum, have been studied by electrophysiological single-sensillum technique and interpreted in terms of a previously reported receptor-interaction model. The results indicate that the terminal methyl group, as well as the acetate group, interacts with highly complementary receptor sites. The terminal alkyl chain is suggested to interact with a hydrophobic "pocket" extending over the two methylene groups closest to the terminal methyl group. The amounts of stimulus actually released from the odor source have been studied. The results demonstrate the necessity to take differences of volatility into account in comparisons of electrophysiological data for compounds of different chain lengths. It is shown that relative vapor pressures may to a good approximation be employed to estimate correction factors.
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| 3. |
- Brisander, Magnus, 1970-
(författare)
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Synthesis and Structure of Novel G-Protein Coupled Receptor Ligands
- 1998
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- A method based on h6-arenetricarbonylchromium chemistry has been developed for the synthesis of enantiopure 4-alkylated 3-(dipropylamino)chromans. The stereochemistry of these new serotonergic ligands was determined by a combination of X-ray crystallography, NMR spectroscopy and chemical correlation. A single-crystal X-ray diffraction study of the hydrochloride salt of the exo-[h 6-(3R)-(dipropylamino)chroman]tricarbonylchromium complex served to determine its relative and absolute configuration, and also as an aid in rationalising the stereochemical outcome of the benzylic alkylations.The stereochemistry of five derivatives of the novel pentacyclic compound (R)-1,11-methyleneaporphine was studied by X-ray diffraction, and their rigid conformation is compared with that of previously published aporphine derivatives.The conformational preferences of two achiral antimuscarinic derivatives of 3-(2-furanyl)quinuclidin-2-ene were studied by experimental (X-ray crystallography) and theoretical methods (ab initio and molecular mechanics). Introduction of a phenyl group in the 3-position of the furan ring causes a steric interaction that changes the conformation and conjugation of the molecule as compared to the 5-phenyl substituted derivative.The relative and absolute configurations of the chiral antimuscarinic stereoisomers of 3-(2,3-dihydrobenzofuran-2-yl)quinuclidine were determined by X-ray diffraction.
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| 4. |
- Fagerström, Alexandra, et al.
(författare)
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Chiral recognition mechanism of cellobiohydrolase Cel7A for ligands based on the β‐blocker propranolol : The effect of explicit water molecules on binding and selectivities
- 2023
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Ingår i: Natural Sciences. - : John Wiley & Sons. - 2698-6248 .- 2698-6248. ; 3:3
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Tidskriftsartikel (refereegranskat)abstract
- Proteins are useful chiral selectors. In order to understand the recognition mechanism and chiral discrimination, the binding of the (R)- and (S)-enantiomers of a series of designed amino alcohol inhibitors based on propranolol to cellobiohydrolase Cel7A (Trichoderma reesei) has been studied more closely. X-ray crystal structures were determined of the protein complex with the (R)- and (S)-enantiomers of the strongest binding propranolol analogue. The combination of the structural data, thermodynamic data from capillary electrophoresis and microcalorimetry experiments and computational modelling give a clearer insight into the origin of the enantioselectivity and its opposite thermodynamic signature. The new crystal structures were used in computational molecular flexible dockings of the propranolol analogues using the program Glide. The results indicated that several water molecules in the active site were essential for the docking of the (R)-enantiomers but not for the (S)-enantiomers. The results are discussed in relation to the enantiomeric discrimination of the enzyme. Both dissociation constants (Kd values) and thermodynamical data are included to show the effects of the structural modifications in the ligand on enthalpy and entropy in relation to the enantioselectivity.
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| 5. |
- Kahnberg, Pia, et al.
(författare)
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Refinement and evaluation of a pharmacophore model for flavone derivatives binding to the benzodiazepine site of the GABA(A) receptor
- 2002
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Ingår i: Journal of Medicinal Chemistry. - 1520-4804. ; 45:19, s. 4188-4201
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Tidskriftsartikel (refereegranskat)abstract
- To further develop and evaluate a pharmacophore model previously proposed by Cook and co-workers (Drug Des. Discovery 1995,12,193-248) for ligands binding to the benzodiazepine site of the GABA(A) receptor, 40 new flavone derivatives have been synthesized and their affinities for the benzodiazepine site have been determined. Two new regions of steric repulsive interactions between ligand and receptor have been characterized, and the receptor region in the vicinity of 6- and 8'-substituents has been mapped out. 2'-Hydroxy substitution is shown to give a significant increase in affinity, which is interpreted in terms of a novel hydrogen bond interaction with the previously proposed hydrogen bond-accepting site A2. On the basis of the results of these studies and the refined pharmacophore model, 5'-bromo-2'-hydroxy-6-methylflavone, the highest affinity flavone derivative reported so far (K-i = 0.9 nM), was successfully designed. A comparison of the pharmacophore model with a recently proposed alternative model (Marder; et al. Bioorg. Med. Chem., 2001, 9, 323-335) has been made.
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| 6. |
- Lager, Erik, et al.
(författare)
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Affinity of 3-acyl substituted 4-quinolones at the benzodiazepine site of GABAA receptors.
- 2008
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Ingår i: Bioorganic & Medicinal Chemistry. - : Elsevier BV. - 0968-0896. ; 16:14, s. 6936-6948
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Tidskriftsartikel (refereegranskat)abstract
- The finding that alkyl 1,4-dihydro-4-oxoquinoline-3-carboxylate and N-alkyl-1,4-dihydro-4-oxoquinoline-3-carboxamide derivatives may be high-affinity ligands at the benzodiazepine binding site of the GABAA receptor, prompted a study of 3-acyl-1,4-dihydro-4-oxoquinoline (3-acyl-4-quinolones). In general, the affinity of the 3-acyl derivatives was found to be comparable with the 3-carboxylate and the 3-carboxamide derivatives, and certain substituents (e.g., benzyl) in position 6 were again shown to be important. As it is believed that the benzodiazepine binding site is situated between an α- and a γ-subunit in the GABAA receptor, selected compounds were tested on the α1β2γ2s, α2β2γ2s and α3β2γ2s GABAA receptor subtypes. The 3-acyl-4-quinolones display various degrees of selectivity for α1- versus α2- and α3-containing receptors, and high-affinity ligands essentially selective for α1 over α3 were developed.
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| 7. |
- Liljefors, Tommy, et al.
(författare)
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Chain-elongated analogues of a pheromone component of the turnip moth, Agrotis segetum. A structure-activity study using molecular mechanics
- 1985
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Ingår i: Journal of the Chemical Society, Perkin Transactions 2. - 1472-779X. ; :12, s. 1957-1962
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Tidskriftsartikel (refereegranskat)abstract
- Chain-elongated analogues of (Z)-dec-5-enyl acetate, a pheromone component of the turnip moth, Agrotis segetum, have been studied. The conformational energies required for the analogues to mimic spatial relationships in the parent molecule, assumed to be crucial for the receptor interaction, were calculated by molecular mechanics (MM2). The calculated energies show a striking correlation with measured single-cell electrophysiological activities. The results indicate that an elongated alkyl chain is conformationally rearranged when the analogue is bound to the receptor, and that the biological activity is determined by the corresponding conformational energy.
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| 8. |
- Nilsson, Jakob, et al.
(författare)
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3-Alkyl- and 3-amido-isothiazoloquinolin-4-ones as ligands for the benzodiazepine site of GABA(A) receptors.
- 2011
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Ingår i: Bioorganic & Medicinal Chemistry Letters. - : Elsevier BV. - 0960-894X.
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Tidskriftsartikel (refereegranskat)abstract
- Based on a pharmacophore model of the benzodiazepine binding site of the GABA(A) receptors, developed with synthetic flavones and potent 3-carbonylquinolin-4-ones, 3-alkyl- and 3-amido-6-methylisothiazoloquinolin-4-ones were designed, prepared and assayed. The suggestion that the interaction between the hydrogen bond donor site H1 with the 3-carbonyl oxygen in 3-carbonylquinolin-4-ones can be replaced by an interaction between H1 and N-2 in the isothiazoloquinolin-4-ones, was confirmed. As with the 3-carbonylquinolin-4-ones, the length of the chain in position 3 is critical for an efficient interaction with the lipophilic pockets of the pharmacophore model. The most potent 3-alkyl derivative, 3-pentyl-6-methylisothiazoloquinolin-4-one, has an affinity (K(i) value) for the benzodiazepine binding site of the GABA(A) receptors of 13nM. However, by replacing the 3-pentyl with a 3-butyramido group an even more potent compound was obtained, with a K(i) value of 2.8nM, indicating that the amide function facilitates additional interactions with the binding site.
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| 9. |
- Nilsson, Jakob, et al.
(författare)
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Azaflavones compared to flavones as ligands to the benzodiazepine binding site of brain GABA(A) receptors.
- 2008
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Ingår i: Bioorganic & Medicinal Chemistry Letters. - : Elsevier BV. - 0960-894X. ; 18:21, s. 5713-5716
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Tidskriftsartikel (refereegranskat)abstract
- A series of azaflavone derivatives and analogues were prepared and evaluated for their affinity to the benzodiazepine binding site of the GABA(A) receptor, and compared to their flavone counterparts. Three of the compounds, the azaflavones 9 and 12 as well as the new flavone 13, were also assayed on GABA(A) receptor subtypes (alpha(1)beta(3)gamma(2s), alpha(2)beta(3)gamma(2s), alpha(4)beta(3)gamma(2s) and alpha(5)beta(3)gamma(2s)), displaying nanomolar affinities as well as selectivity for alpha1- versus alpha2- and alpha3-containing receptors by a factor of between 14 and 26.
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| 10. |
- Nilsson, Jakob, et al.
(författare)
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Triazoloquinazolinediones as novel high affinity ligands for the benzodiazepine site of GABA(A) receptors.
- 2011
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Ingår i: Bioorganic & Medicinal Chemistry. - : Elsevier BV. - 0968-0896. ; 19:1, s. 111-121
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Tidskriftsartikel (refereegranskat)abstract
- Based on a pharmacophore model of the benzodiazepine-binding site of GABA(A) receptors, a series of 2-aryl-2,6-dihydro[1,2,4]triazolo[4,3-c]quinazoline-3,5-diones (structure type I) were designed, synthesized, and identified as high-affinity ligands of the binding site. For several compounds, K(i) values of around 0.20nM were determined. They show a structural resemblance with the previously described 2-phenyl-2H-pyrazolo[4,3-c]quinolin-3(5H)-ones (II) and 2-phenyl-[1,2,4]triazolo[1,5-a]quinoxalin-4(5H)-one (III). The 9-bromo substituted compounds 8a-d were prepared in an 8-step synthesis in an overall yield of approximately 40%, and a library of 9-substituted analogues was prepared by cross-coupling reactions. Compound 8e, 21, 22, and 24 were tested on recombinant rat α(1)β(3)γ(2), α(2)β(3)γ(2), α(3)β(3)γ(2), and α(5)β(3)γ(2) subtypes, and displayed selectivity for the α(1)β(3)γ(2) isoform.
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