Abstract
Given the paucity of antiviral treatments for monkeypox disease, caused by the Monkeypox virus (MPXV), there is a pressing need for the development/identification of new drugs to treat the infection. MPXV possesses a linear dsDNA genome that is replicated by a DNA replication complex of which DNA polymerase (DPol) forms an important component. Owing to the importance of DPol in the viral life cycle, identifying/designing small molecules abolishing its function could yield new antivirals. In this study, we first used the AlphaFold artificial intelligence program to model the 3D structure of the MPXV DPol; like the fold of DPol from other organisms, the MPXV DPol structure has the characteristic exonuclease, thumb, palm, and fingers sub-domains arrangement. Subsequently, we have identified several inhibitors through virtual screening of ZINC and antiviral libraries. Molecules with phenyl scaffold along with alanine-based and tetrazole-based molecules showed the best docking score of -8 to -10 kcal/mol. These molecules bind in the palm and fingers sub-domains interface region, which partially overlaps with the DNA binding path. The delineation of DPol/inhibitor interactions showed that majorly active site residues ASP549, ASP753, TYR550, ASN551, SER552, and ASN665 interact with the inhibitors. These compounds exhibit good Absorption, Distribution, Metabolism and Excretion properties.