A Molecular Simulation Study of Sulfonamide HBV Core Protein Allosteric Modulators

Abstract In recent years, hepatitis B virus (HBV) core protein allosteric modulators (CpAMs) have become a hot spot to develop new anti‐HBV drugs. Sulfonamide analogues are a new class of CpAMs targeting HBV core protein (Cp), while their biological activity is still needed to be improved and the binding mechanism is unclear still. In this study, we utilized molecular docking and molecular dynamics simulation to explore the binding mode between the novel compounds and HBV Cp. Combining with binding free energy calculation and decomposition, we inferred that TyrE132, ValE124, ThrE128, ThrD109, and IleD105 were key residues during the binding process, and especially, the conformational change of TryE132 was responsible for the stable binding. Besides, reasonable CoMFA ( q 2 = 0.515, r 2 ncv = 0.994, and r 2 pred = 0.628) and CoMSIA ( q 2 = 0.602, r 2 ncv = 0.988, and r 2 pred = 0.681) models were constructed to explore the 3D structure‐activity relationship of the novel compounds. The results suggested that it was favorable to increase the biological activity of sulfonamide analogues when introducing hydrophobic groups to R 1 and electronegative groups to R 2 . In conclusion, we explored the binding mode and structure‐activity relationship between sulfonamides and HBV Cp and provided a theoretical basis for the optimization of this series of compounds.