Multiple e-pharmacophore modeling, 3D-QSAR, and high-throughput virtual screening of hepatitis C virus NS5B polymerase inhibitors.
The hepatitis C virus (HCV) NS5B RNA-dependent RNA polymerase (RdRP) is a crucial and unique component of the HCV RNA replication machinery and a validated target for drug discovery. Multiple crystal structures of NS5B inhibitor complexes have facilitated the identification of novel compound scaffolds through in silico analysis. With the goal of discovering new NS5B inhibitor leads, HCV NS5B crystal structures bound with inhibitors in the palm and thumb allosteric pockets in combination with ligands with known inhibitory potential were explored for a comparative pharmacophore analyses. The energy-based and 3D-QSAR-based pharmacophore models were validated using enrichment analysis, and the six models thus developed were employed for high-throughput virtual screening and docking to identify nonpeptidic leads. The hits derived at each stage were analyzed for diversity based on the six pharmacophore models, followed by molecular docking and filtering based on their interaction with amino acids in the NS5B allosteric pocket and 3D-QSAR predictions. The resulting 10 hits displaying diverse scaffold were then screened employing biochemical and cell-based NS5B and anti-HCV inhibition assays. Of these, two molecules H-5 and H-6 were the most promising, exhibiting IC50 values of 28.8 and 47.3 μM against NS5B polymerase and anti-HCV inhibition of 96% and 86% at 50 μM, respectively. The identified leads comprised of benzimidazole (H-5) and pyridine (H-6) scaffolds thus constitute prototypical molecules for further optimization and development as NS5B inhibitors.
Computer-Aided Drug Design Lab, Department of Pharmacy, Birla Institute of Technology & Science-Pilani , Hyderabad campus, Jawahar Nagar, Hyderabad-500078, Andhra Pradesh, India.
Patrisha Joseph
PJ
Therese
Dinesh
D
Manvar
Sridevi
S
Kondepudi
Madhu Babu
MB
Battu
Dharmarajan
D
Sriram
Amartya
A
Basu
Perumal
P
Yogeeswari
Neerja
N
Kaushik-Basu
D000998:Antiviral Agents / Q000009:adverse effects / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D002460:Cell Line; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000009:adverse effects / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D016174:Hepacivirus / Q000187:drug effects / Q000201:enzymology*; D057166:High-Throughput Screening Assays; D006801:Humans; D062105:Molecular Docking Simulation; D011487:Protein Conformation; D021281:Quantitative Structure-Activity Relationship; D013816:Thermodynamics; D014584:User-Computer Interface; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D012324:RNA-Dependent RNA Polymerase
D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase