Discovery of a Potential Inhibitor Against A42R Profilin-like Protein of Monkeypox Virus through In Silico High-throughput Screening
Abstract
Monkeypox (Mpox) outbreak is a worldwide challenge, and recent reports are indicating its quick spread in certain regions, especially Africa, and new cases emerging in other countries. World Health Organization declared it as emergency concern for public health in 2024 due to a new clade epidemic in Africa. As of late 2025, there are no FDA-approved medications to treat monkeypox, however some antiviral drugs are utilized to treat severe cases or people at high risk of critical illness. 3D structure of A42R was retrieved from protein data bank, and 6000 antiviral compounds were downloaded from Asinex database to dock them against target protein. Pharmacokinetic properties of hit compounds were corroborated using ADME/T profiles. Through High Throughput Virtual Screening (HTVS) and molecular docking, top hit from virtual screening and ADME/T analysis, was selected. Ligand-A42R docked complex revealed Ala81 and Glu83 residues involved in H-bonding and Tyr118, Arg 119 & 115 in Pi-Pi stacking interactions within binding pocket of A42R. Binding free energy of -46.79 Kcal/mol, calculated through MM-GBSA, designated lead candidate as strong inhibitor against Profilin-like-protein. Receptor based HTVS suggested C21H24ClNO4 as lead compound having glide score of -6.066. Studies have reported the discovery of therapeutic compounds against A42R protein using computational techniques. After screening antiviral compounds, lead compound was found to have favourable properties that make it strong inhibitory molecule against A42R protein. However, in-vitro and in-vivo testing is still indispensable to validate the clinical efficacy, large scale productivity, and competency of the designed antiviral therapeutics. Simulation studies established promising potential of the compound as an effective inhibitor of A42R protein and prospective use in management of Mpox disease. Further, studies are indispensable to confirm our outcome and determine compound's efficacy and safety.