Molecular Docking and Pharmacophore-Based Virtual Screening of Novel Inhibitors for HCV NS5B RNA-Dependent RNA Polymerase Enzyme from Crude Sesame Essential Oil.

Abstract

Concern has been expressed worldwide about the rising prevalence of HCV induced acute hepatitis and chronic liver diseases with associated cirrhosis and liver cancers. However, the available synthetic drugs are ineffective for all the HCV genotypes especially in genotype-1 patients with about 40% viral response rates and numerous side effects. Besides, the availability of veritable bioinformatics tools which includes molecular docking and virtual screening studies have shown that computational generated models nowadays assists in modern drug design and development of novel and more potent inhibitors through the understanding of protein (receptors) -ligand (drugs) interaction mechanisms. Non-structural proteins especially the 5B (NS5B) is an RNA-dependent RNA polymerase implicated in the synthesis and replication of the HCV RNA; and has been a potential target for its inhibitory activities. Due to the paucity of knowledge, we aimed to determine the differential inhibitory activity of essential oils present in the crude Sesame leaves extracts on HCV-NS5B RNA dependent RNA polymerase. Using in-silico studies- a Microsoft pharmacophore-based virtual screening and molecular docking tools on the iGEMDOCK vs 2.0 software was used to dock the essential oil ligands on the generated HCV NS5B (PDB ID: 4EO6) RNA-dependent RNA polymerase protein. GC-MS of the leaves confirmed carboxylic acids and phenolic groups in the essential oils especially some potent antioxidants like alpha-linolenic acid, linoleic acid, oleic acid, etc. Moreover, Alpha-Linolenic acid/ALA (-102.2/-103.4 kcal/mol) and Linoleic acid/LA (-94.8/-109.8 kcal/mol) showed higher inhibitory impacts among the six top different docked ligands, selected based on their high differential binding affinity and pharmacological interaction energy profiles against HCV NS5B RNA polymerase activities, by forming more H-bond interactions than the NS5B co-crystallized ligand. ADMET showed that ALA is well tolerated without any apparent toxicity in the body. Hence, ALA having the highest inhibitory impacts against the HCV NS5B goes to confirm the beneficial impacts of carboxylic acids from Sesame plant in maintaining liver cellular integrity and as a natural inhibitor of HCV NS5B RNA dependent RNA Polymerase enzyme activities.