Molecular Dynamics Simulation, Molecular Docking, ADMET prediction, QSAR modeling and density functional theory computation for the identification of possible Hepatitis C Virus NS5B Protease inhibitors through in silico study of fluorine-2, 7-diamine compounds
Abubakar Sadiq Bello, Adamu Uzairu, Shallangwa G. Aadmu, Abdulkadir ibrahim, A. A. Razzak Mahmood, Muhammad Tukur Ibrahim · In Silico Research in Biomedicine · 2025
The hepatitis C virus is known to lead to liver conditions such as cirrhosis and hepatocellular carcinoma, prompting ongoing therapeutic advancements. Recent studies highlight the growing significance of plant-derived compounds in developing innovative and cost-effective anti-Hepatitis C treatments. This research scrutinized 32 fluorine-2,7-diamine compounds using in-silico methods, including 2D-3D QSAR modeling and molecular docking, supported by ADMET assessment and DFT calculations. A robust 2D QSAR model (R2 external = 0.5193, R2 internal = 0.6427) was established and validated, with compound 12 emerging as a top candidate based on a high molecular docking score of -228.663 kcal/mol. Moreover, six novel compounds, particularly SCD6 exhibiting a superior molecular docking score of -241.463 kcal/mol towards the NS5B polymerase, were developed through a structure-based strategy. Molecular Dynamics simulations of SCD2-3FQK and SCD6-3FQK complexes displayed stable interactions with RMSD values of 1.79 Å and 2.00 Å. MM-GBSA analysis confirmed the stronger binding affinity of SCD6-3FQK (-117.85 ± 12.48 kcal/mol) compared to SCD2-3FQK (-97.95 ± 14.94 kcal/mol), underlining their robust interaction profiles. The newly synthesized compounds exhibit favorable pharmacokinetic properties, with a bioavailability score of 0.55 and excellent synthetic accessibility, indicating their potential for wet-lab production. Among these, SCD6 emerges as a stable molecule with superior affinity and promising pharmacokinetic attributes, making it a prime candidate for further development as a prospective Hepatitis C therapeutic agent.