Computational Medicinal Chemistry applications to cure Asian-prevalent strain of Hepatitis C Virus

Abstract

Hepatitis C Virus (HCV), affecting millions of people worldwide, is the leading cause of the liver disorder, cirrhosis, and hepatocellular carcinoma. HCV is genetically diverse having eight gen-otypes and several subtypes predominant in different regions of the globe. The HCV NS3/4A protease is a primary therapeutic target for HCV with various FDA-approved antivirals and several clinical developments. However, available protease inhibitors (PIs) have lower potency against HCV genotype 3 (GT3), prevalent in South Asia. In this study, the incumbent computational tools were utilized to understand and explore interactions of the HCV GT3 receptor with the potential inhibitors after the virtual screening of one million compounds retrieved from the ZINC database. The molecular dynamics, pharmacological studies, and experimental studies uncovered the potential PIs as ZINC000224449889, ZINC000224374291, and ZINC000224374456 and derivative of ZINC000224374456 from the ZINC library. The study revealed that these top hit compounds exhibited good binding and better pharmacokinetics properties that might be considered the most promising compound against HCV GT3 protease. Viability test, on primary healthy Human Gingival Fibroblasts (HGFs) and cancerous AGS cell line were also performed to assess their safety profile after administration. In addition, Surface Plasmon Resonance (SPR) was also performed for determination of affinity and kinetics of synthesized compounds with target proteins.

Computational Pharmaceutics: A Comprehensive Review of Past Achievements, Present Applications, and Future Challenges

“…Computational pharmaceutics involves utilizing computational modeling techniques to understand drug delivery mechanisms and develop new delivery systems. (Ouyang & Smith, 2015;Sadiku et al, 2019) It encompasses molecular modeling for rational drug design, compound screening, and studying formulation at a molecular level (Hussain et al, 2023;Ouyang & Smith, 2015). This field explores various drug delivery systems like cyclodextrins, liposomes, and polymeric systems.…”

“…Computational pharmaceutics plays a pivotal role in modern drug discovery and formulation development (Hussain et al, 2023). By utilizing computational models and simulations, researchers can gain insights into molecular interactions, drug delivery mechanisms, and formulation behaviors (Sadiku et al, 2019).…”