MOLECULAR MODELING AND VIRTUAL SCREENING FOR COMPUTER-AIDED DESIGN OF HCV NS5B POLYMERASE INHIBITORS

Bertrand-Ulrich Yavo; Akori Elvice Esmel; Kouakou Jean-Louis Kouakou; Melalie Kéita; Megnassan Eugène

doi:10.22270/ujpr.v11i3.1586

Bertrand-Ulrich Yavo Laboratory of Fundamental and Applied Physics, UFR SFA, Nangui Abrogoua University, BP 801 Abidjan 02, Côte d’Ivoire.
Akori Elvice Esmel Laboratory of Fundamental and Applied Physics, UFR SFA, Nangui Abrogoua University, BP 801 Abidjan 02, Côte d’Ivoire.
Kouakou Jean-Louis Kouakou Laboratory of Fundamental and Applied Physics, UFR SFA, Nangui Abrogoua University, BP 801 Abidjan 02, Côte d’Ivoire.
Melalie Kéita Laboratory of Fundamental and Applied Physics, UFR SFA, Nangui Abrogoua University, BP 801 Abidjan 02, Côte d’Ivoire.
Megnassan Eugène Laboratory of Fundamental and Applied Physics, UFR SFA, Nangui Abrogoua University, BP 801 Abidjan 02, Côte d’Ivoire. ICTP-UNESCO, QLS, Strada Costiera, 11, I-34151, Trieste, Italy.

10.22270/ujpr.v11i3.1586

Keywords:

Computer-aided rational design, inhibitors, molecular dynamics, NS5B polymerase, pharmacophore, QSAR, quinazolinone derivatives, virtual screening

Abstract

Aims and objectives: This study aims to design new inhibitors for the Hepatitis C Virus (HCV) Non-Structural Protein 5B (NS5B) polymerase, an enzyme essential for viral replication. The research addresses an urgent public health issue affecting 71 million people and causing approximately 242,000 deaths annually.

Methodology: The research follows a computer-aided rational design approach. A Quantitative Structure-Activity Relationship (QSAR) model was developed using 24 quinazolinone derivatives (QDs) to correlate Gibbs free energy with experimental inhibition constants. The bound conformations of the ligands were used to construct a 3D-QSAR pharmacophore (PH4) model. A virtual library of 168,750 QDs was generated and filtered using ADME (Absorption, Distribution, Metabolism, and Excretion) criteria and PH4 screening. Conformational stability was evaluated through 200-ns molecular dynamics (MD) simulations. Binding free energy variations were quantified using the Molecular Mechanics - Generalized Born Surface Area (MM-GBSA) approach on MD trajectories, calculating molecular mechanics energy, solvation energy, and surface area contributions under the OPLS2005 force field.

Results: The QSAR model showed high predictive power and the PH4 model achieved an R² of 0.85. Screening identified 39 potent analogues. The lead candidate, 3-6-4-45, exhibited a predicted inhibitory concentration of 0.62 nM, approximately 96 times more active than the best reference ligand (60 nM). MD simulations confirmed stability with RMSD values between 1.5 and 3 Å. MM-GBSA binding energies converged with predicted complexation energies, validating the computational reliability.

Conclusion: The integration of molecular modeling and in silico screening successfully identified six potent candidate inhibitors of the HCV NS5B polymerase with favorable pharmacokinetic profiles. These analogues represent high-affinity candidates for future therapeutic development.