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Lead expansion and virtual screening of Indinavir derivate HIV-1 protease inhibitors using pharmacophoric - shape similarity scoring function.

Shityakov S, Dandekar T - Bioinformation (2010)

Bottom Line: However, it becomes less effective due to highly resistant new viral strains of HIV, which have multiple mutations in their proteases.For this reason, we used a lead expansion method to create a new set of compounds with a new mode of action to protease binding site. 1300 compounds chemically diverse from the initial hit were generated and screened to determine their ability to interact with protease and establish their QSAR properties.Further computational analyses revealed one unique compound with different protease binding ability from the initial hit and its role for possible new class of protease inhibitors is discussed in this report.

View Article: PubMed Central - PubMed

Affiliation: Department of Bioinformatics, Biocenter of the University of Würzburg, 97074 Würzburg, Germany. shityakov@vim.uni-wuerzburg.de

ABSTRACT
Indinavir (Crivaxan®) is a potent inhibitor of the HIV (human immunodeficiency virus) protease. This enzyme has an important role in viral replication and is considered to be very attractive target for new antiretroviral drugs. However, it becomes less effective due to highly resistant new viral strains of HIV, which have multiple mutations in their proteases. For this reason, we used a lead expansion method to create a new set of compounds with a new mode of action to protease binding site. 1300 compounds chemically diverse from the initial hit were generated and screened to determine their ability to interact with protease and establish their QSAR properties. Further computational analyses revealed one unique compound with different protease binding ability from the initial hit and its role for possible new class of protease inhibitors is discussed in this report.

No MeSH data available.


Related in: MedlinePlus

(A) Indinavir and (B) novel hit docking profiles calculated by AutoDock software. Both ligands are gray. HIV protease chain A and Bamino acids are painted in green and magenta respectively. The hydrogen bonds are shown for each of both molecules; see text for details.
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Figure 3: (A) Indinavir and (B) novel hit docking profiles calculated by AutoDock software. Both ligands are gray. HIV protease chain A and Bamino acids are painted in green and magenta respectively. The hydrogen bonds are shown for each of both molecules; see text for details.

Mentions: Probably this acceptor nitrile group along with the tetrahydropyridinering might have some influence on the ligand conformational shiftwith subsequent change in binding affinity mode. In both dockingcases, the catalytic function of the Asp 25 residues is completelyblocked. Subsequently, we performed the AutoDock experiments tovalidate the above data and revealed reduction in hydrogen bondsformation presumably due to differences in affinity grid resolution ofMolegro Virtual Docker and AutoDock (0.3 vs 0.375 Å). However,consistent with previous observation, all crucial amino acids obtainedfrom Molegro docking experiments are also present in the AutoDockdocking profiles (Figure 3(A,B)).The IDV spatial conformationrecruits less docking energy (-15.1 kcal/mol) in comparison to novelhit and forms H-bonds with amino acid residues of chain B. In thisorientation, the amide nitrogen donor together with carboxyl group(hydroxyl moiety) of the Asp 29 residue, the Asp 25 carboxyl group(hydroxyl moiety) and the Gly 27 amide oxygen acceptor makehydrogen bonds with two hydroxyl functional groups and one amidenitrogen donor of the ligand molecule.


Lead expansion and virtual screening of Indinavir derivate HIV-1 protease inhibitors using pharmacophoric - shape similarity scoring function.

Shityakov S, Dandekar T - Bioinformation (2010)

(A) Indinavir and (B) novel hit docking profiles calculated by AutoDock software. Both ligands are gray. HIV protease chain A and Bamino acids are painted in green and magenta respectively. The hydrogen bonds are shown for each of both molecules; see text for details.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2957763&req=5

Figure 3: (A) Indinavir and (B) novel hit docking profiles calculated by AutoDock software. Both ligands are gray. HIV protease chain A and Bamino acids are painted in green and magenta respectively. The hydrogen bonds are shown for each of both molecules; see text for details.
Mentions: Probably this acceptor nitrile group along with the tetrahydropyridinering might have some influence on the ligand conformational shiftwith subsequent change in binding affinity mode. In both dockingcases, the catalytic function of the Asp 25 residues is completelyblocked. Subsequently, we performed the AutoDock experiments tovalidate the above data and revealed reduction in hydrogen bondsformation presumably due to differences in affinity grid resolution ofMolegro Virtual Docker and AutoDock (0.3 vs 0.375 Å). However,consistent with previous observation, all crucial amino acids obtainedfrom Molegro docking experiments are also present in the AutoDockdocking profiles (Figure 3(A,B)).The IDV spatial conformationrecruits less docking energy (-15.1 kcal/mol) in comparison to novelhit and forms H-bonds with amino acid residues of chain B. In thisorientation, the amide nitrogen donor together with carboxyl group(hydroxyl moiety) of the Asp 29 residue, the Asp 25 carboxyl group(hydroxyl moiety) and the Gly 27 amide oxygen acceptor makehydrogen bonds with two hydroxyl functional groups and one amidenitrogen donor of the ligand molecule.

Bottom Line: However, it becomes less effective due to highly resistant new viral strains of HIV, which have multiple mutations in their proteases.For this reason, we used a lead expansion method to create a new set of compounds with a new mode of action to protease binding site. 1300 compounds chemically diverse from the initial hit were generated and screened to determine their ability to interact with protease and establish their QSAR properties.Further computational analyses revealed one unique compound with different protease binding ability from the initial hit and its role for possible new class of protease inhibitors is discussed in this report.

View Article: PubMed Central - PubMed

Affiliation: Department of Bioinformatics, Biocenter of the University of Würzburg, 97074 Würzburg, Germany. shityakov@vim.uni-wuerzburg.de

ABSTRACT
Indinavir (Crivaxan®) is a potent inhibitor of the HIV (human immunodeficiency virus) protease. This enzyme has an important role in viral replication and is considered to be very attractive target for new antiretroviral drugs. However, it becomes less effective due to highly resistant new viral strains of HIV, which have multiple mutations in their proteases. For this reason, we used a lead expansion method to create a new set of compounds with a new mode of action to protease binding site. 1300 compounds chemically diverse from the initial hit were generated and screened to determine their ability to interact with protease and establish their QSAR properties. Further computational analyses revealed one unique compound with different protease binding ability from the initial hit and its role for possible new class of protease inhibitors is discussed in this report.

No MeSH data available.


Related in: MedlinePlus