Abstract: The purpose of this study is to screen potential inhibitors targeting monkeypox virus A42R protein through drug reuse strategy to solve the current lack of specific anti-monkeypox drugs. 6 candidate compounds with good binding ability to A42R were screened from 9803 small molecules in the ZINC database by molecular docking, molecular dynamics simulation and MM/PBSA(Molecular Mechanics/Poisson-Boltzmann Surface Area) binding free energy calculation. Among them, ZINC000000538152 with two negative charges has the strongest binding ability (-236.3 kJ/mol). It forms multiple salt bridges, hydrogen bonds and π-cation interactions with the arginine-rich domain of the A42R protein, which significantly enhances the binding stability. In addition, although ZINC000003935130 is a neutral molecule, it achieves a sub-high binding strength (-102.7 kJ/mol) through strong van der Waals interaction, which is greater than the other three compounds with a negative charge. The conclusion shows that these six compounds are highly potential and can be reused as candidates for A42R inhibitors, because their presence blocks the binding of A42R to actin or PIP2(phosphatidylinositol-(4,5)-bisphosphate), thereby inhibiting virus spread. This study provides new ideas for the development of monkeypox virus drugs.

Key words: Monkeypox virus, A42R protein, Drug repurposing, Blocking mechanism; Molecular dynamics