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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) HIV protease catalytic tunnel (binding site) was predicted by PyMol CAVER module. IDV (B) and novel hit (C) interactions withthe HIV-1 protease are shown. H-bonds are depicted as dashed lines. IDV – protease complex was analyzed as a crystal structure. 3D alignmentand ‘fuzzy’ model (D) of the hit ‘native’ conformation (gray) together with its ‘functional’ conformation (yellow) at 2.0 Å RMSD. The shownpotential pharmacophore points are color-coded as follows: lipophilic areas are green, H-bond donors and acceptors are colored in blue and redrespectively.
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Figure 2: (A) HIV protease catalytic tunnel (binding site) was predicted by PyMol CAVER module. IDV (B) and novel hit (C) interactions withthe HIV-1 protease are shown. H-bonds are depicted as dashed lines. IDV – protease complex was analyzed as a crystal structure. 3D alignmentand ‘fuzzy’ model (D) of the hit ‘native’ conformation (gray) together with its ‘functional’ conformation (yellow) at 2.0 Å RMSD. The shownpotential pharmacophore points are color-coded as follows: lipophilic areas are green, H-bond donors and acceptors are colored in blue and redrespectively.

Mentions: Protein binding surfaces could have very complicated and irregularstructures. Atoms could form pockets, cavities and tunnels. Solventmolecules can get into these tunnels from outer environment and movethrough them. Buried shape and volume of such tunnels vary in timedue to protein dynamics and kinetics. Here, we analyzed buriedtunnels of the protease using the CAVER module, to identify certainatomic positions of hidden binding moieties [13]. Dijkstra's algorithmwas implemented in searching process and started from source node(starting point), which is located deeply in the protein pocket. Beforethe search procedure, 136 water molecules, chloride and sodium ionswere removed from IDV-bound protease (liganded holo-structure)protein database file. All calculations were performed on 32612 gridpoints. Catalytic tunnel (key interaction site) was detected in theprotease structure ((Figure 2(A)). The tunnel coordinates to specify thestarting point in x, y and z axis are 2.5, 6.5, -7.5 respectively. Thesecoordinates were taken from the AutoDock manual [14].IDV


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) HIV protease catalytic tunnel (binding site) was predicted by PyMol CAVER module. IDV (B) and novel hit (C) interactions withthe HIV-1 protease are shown. H-bonds are depicted as dashed lines. IDV – protease complex was analyzed as a crystal structure. 3D alignmentand ‘fuzzy’ model (D) of the hit ‘native’ conformation (gray) together with its ‘functional’ conformation (yellow) at 2.0 Å RMSD. The shownpotential pharmacophore points are color-coded as follows: lipophilic areas are green, H-bond donors and acceptors are colored in blue and redrespectively.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2957763&req=5

Figure 2: (A) HIV protease catalytic tunnel (binding site) was predicted by PyMol CAVER module. IDV (B) and novel hit (C) interactions withthe HIV-1 protease are shown. H-bonds are depicted as dashed lines. IDV – protease complex was analyzed as a crystal structure. 3D alignmentand ‘fuzzy’ model (D) of the hit ‘native’ conformation (gray) together with its ‘functional’ conformation (yellow) at 2.0 Å RMSD. The shownpotential pharmacophore points are color-coded as follows: lipophilic areas are green, H-bond donors and acceptors are colored in blue and redrespectively.
Mentions: Protein binding surfaces could have very complicated and irregularstructures. Atoms could form pockets, cavities and tunnels. Solventmolecules can get into these tunnels from outer environment and movethrough them. Buried shape and volume of such tunnels vary in timedue to protein dynamics and kinetics. Here, we analyzed buriedtunnels of the protease using the CAVER module, to identify certainatomic positions of hidden binding moieties [13]. Dijkstra's algorithmwas implemented in searching process and started from source node(starting point), which is located deeply in the protein pocket. Beforethe search procedure, 136 water molecules, chloride and sodium ionswere removed from IDV-bound protease (liganded holo-structure)protein database file. All calculations were performed on 32612 gridpoints. Catalytic tunnel (key interaction site) was detected in theprotease structure ((Figure 2(A)). The tunnel coordinates to specify thestarting point in x, y and z axis are 2.5, 6.5, -7.5 respectively. Thesecoordinates were taken from the AutoDock manual [14].IDV

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