Serine/threonine kinase of human Monkeypox virus: computational modeling and structural analysis

Abstract Kinases catalyze phosphoryl transfer from a nucleoside triphosphate (usually ATP) to an amino acid residue on a protein (for activation purposes). These enzymes are well-appreciated drug targets against different viruses and cancers. However, some poxviruses are human and animal pathogens that lack effective therapeutic agents. In poxvirus, the production of infectious particles in the infected cells depends on F10 protein kinase that activates numerous proteins involved in the assembly of new virions. The ongoing outbreak of the human monkeypox virus (hMPXV) sparked the need for efficient antiviral drugs to control such outbreaks and lower their burden. In this work, we employed state-of-the-art computational resources to elucidate the structure of the major kinase in hMPXV using AlphaFold2. The predicted structure shows the atypical nature of this kinase; nonetheless, the overall structural fold is roughly conserved. Calculations of binding free energy determined the hotspot residues contributing to phosphate source (ATP) via Molecular Mechanics with Generalized Born and Surface Area solvation (MM/GBSA). The structural analysis in this work provides the basis for setting up a thorough experimental investigation to understand the enzymatic mechanism and development of small-molecule inhibitors against such a critical target.