IDX-184 is a superior HCV direct-acting antiviral drug: a QSAR study

Abstract

Quantitative structure-activity relationship (QSAR) parameters are good indicators for the reactivity of direct-acting antiviral drugs. Since molecular structure is related to molecular function, careful selection of molecular substitutions will result in more drugs that are potent. In this work, QSAR parameters are selected in order to compare the four drugs used as nucleotide inhibitors (NIs) for non-structural 5B (NS5B) RNA-dependent RNA polymerase (RdRp) of hepatitis C virus (HCV). These drugs are: ribavirin (widely used over the last 20 years), sofosbuvir (approved on December 2013 by FDA), and finally IDX-184 and R7128 (phase IIb of clinical trial drugs). The nucleotide analogues uracil (U), guanine (G), and cytosine (C) from which these drugs are fabricated are also compared to that group of drugs. QSAR parameters suggested that the drug IDX-184 is the best among all of the studied NIs. It also shows that NIs are always more reactive than their parent nucleotide.

Quantitative structure‐activity relationship and molecular docking revealed a potency of anti‐hepatitis C virus drugs against human corona viruses

“…Table shows some parameters that reflect the stability of the structures (dielectric energy, steric energy, heat of formation, and the frontier energy gap [LUMO‐HOMO energy]) while Table shows other parameters that reflect the reactivity of the structures (dipole moment, electron affinity, molar refractivity, polarizability, Log P, and solvent accessible surface area) …”

“…Computer Aided Drug Design (CADD) is the utilization of computer software to mimic, visualize, and characterize the behavior of biological molecules. It often uses molecular modeling in conjunction with Quantitative Structure‐Activity Relationship (QSAR) in order to test the reactivity of a ligand and its binding pattern into protein active site . Molecular docking is usually used in order to mimic the binding of a ligand into protein active site using a scoring function.…”

Anti-HCV, nucleotide inhibitors, repurposing against COVID-19

“…RdRp is a crucial enzyme in the life cycle of RNA viruses, including coronaviruses. RdRp is targeted in different RNA viruses, including Hepatitis C Virus (HCV), Zika Virus (ZIKV), and coronaviruses (CoVs) [16][17][18][19][20][21][22][23][24]. The active site of RdRp is highly conserved representing two successive aspartate residues protruding from a beta-turn structure making them surface accessible through the nucleotide channel (free nucleotides can pass through) Several in vitro and clinical trials started in China during the last month with the first approved drug, Favilavir, by the National Medical Products Administration of China is announced yesterday (18 February 2020) in Zhejiang province.…”

Perspectives towards antiviral drug discovery against Ebola virus

“…Molecular substitutions that are closely linked with the molecular properties can guide the design of such scaffolds. Several studies are reporting the use of quantitative structure‐activity relationship modeling in lead optimization …”