Quantum modelling analysis of some potent indole derivatives on NS5B polymerase inhibitors

Viral hepatitis C infection is one of the main causes of the hepatitis after blood transfusion, hepatitis C virus (HCV) infection is a global health threat. The Non-structural viral protein (NS5B) is one of the best-studied polymerase which emerged as an attractive target for the development of novel therapeutics against hepatitis C virus. Quantitative structure-activity relationship studies (QSAR) was carried out on a series of indole derivatives as anti-hepatitis C inhibitors. Density Functional Theory (DFT) quantum chemical calculation method was used to find the optimized geometry of the indole inhibitors. Five types of molecular descriptors were used to derive a quantitative relation between indole activity and structural properties. The relevant molecular descriptors were selected by Genetic Function Algorithm (GFA). The best model (model 1) was validated and found to be statistically significant with squared correlation coefficient of R2 of 0.969, R2adj value 0.917, and Q2 LOO 0.612 and the external validation was found to be R2 pred. = 0.815. The proposed model has good stability, robustness, and predictability on verifying with internal and external validation. The physicochemical parameters are to be considered when improving the inhibitory activities of the indole derivatives against an enzyme that causes HCV (NS5B polymerase)

Quantitative structure-activity relationship and molecular docking studies of some series of imidazole derivatives as anti-hepatitis C drug

Hepatitis C virus (HCV) NS5B RNA-depended-RNA-polymerase (RdRp) is an essential enzyme in HCV viral replication and has no functional equivalent in mammalian cells. In silico study was carried out to develop a Quantitative structure activity-relationship and molecular docking on some selected imidazole derivatives as anti-hepatitis C compounds. Density functional theory with B3LYP/6-311G* was employed for complete geometry optimization Five QSAR models were generated using Genetic Function Algorithm (GFA) of the material studio software version 8, in which model one (1) was selected as the best model and reported based on the validation parameter with the squared correlation coefficient (R2) of 0.7114. Adjusted squared correlation coefficient (R2 adj) value 0f 0.6458 and cross-validation coefficient (Q2) LOO 0.5810. The best model that is model (1) was subjected to external validation and was found to be R2 pred. = 0.5729. The result obtained from molecular docking studies shows that the compound with the best binding affinity of -10.7 Kcal/mol formed hydrogen bonding of (GLN 446 and GLU143) and hydrophobic interaction with the amino acid residues of  the Non-Structural 5B polymerase(NS5B polymerase) receptor. The QSAR model and molecular docking results propose the direction of designing new imidazole derivatives agent with better activity against the NS5B polymerase target site.Keywords: Binding affinity, HCV, imidazole, molecular docking, NS5B polymerase, QSA