Identification of potential inhibitors for HCV NS3 genotype 4a by combining protein-ligand interaction fingerprint, 3D pharmacophore, docking, and dynamic simulation

Journal of Biomolecular Structure & Dynamics
Mahmoud Abd El-Monem El-HasabTarek Faathy El-Moselhy

Abstract

HCV NS3 protease domain has been one of the most attractive targets for developing new drugs for HCV infection and many drugs were successfully developed, but all of them were designed for targeting HCV genotype 1 infection. HCV genotype 4a dominant in Egypt has paid less attention. Here, we describe our protocol of virtual screening in identification of novel potential potent inhibitors for HCV NS3 of genotype 4a using homology modeling, PLIF (protein-ligand interaction fingerprint), docking, pharmacophore, and dynamic simulation. A high-quality 3D model of HCV NS3 protease of genotype 4a was constructed using crystal structure of HCV NS3 protease of genotype 1b (PDB ID: 4u01) as a template. PLIF was generated using five crystal structures of HCV NS3 (PDB ID: 4u01, 3kee, 4ktc, 4i33, and 5epn) which revealed the most important residues and their interactions with the co-crystalized ligands. A 3D pharmacophore model consisting of six features was developed from the generated PLIF data and then used as a screening filter for 11,244 compounds. Only 423 compounds passed the pharmacophore filter and entered the docking-based virtual screening stage. The highest ranked five hits from docking result (compound (C1-C5)) were selected fo...Continue Reading

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Citations

May 11, 2019·Current Topics in Medicinal Chemistry·Renata P C BarrosMarcus T Scotti
May 7, 2019·Journal of Biomolecular Structure & Dynamics·Lovika MittalShailendra Asthana
Oct 30, 2020·Journal of Biomolecular Structure & Dynamics·Ismail HdoufaneDriss Cherqaoui
Nov 25, 2021·Future Medicinal Chemistry·Abdulrahim R HakamiMohammed Y Ghazwani

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Datasets Mentioned

BETA
O39929

Software Mentioned

ERRAT
discovery
CHARMM36
Auto Dock Vina
VMD
Query Generator
NAMD
Parachem
CHARMM27
Verify

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