Exploring Chemical Space to Identify Partial Binders Against hMPV Nucleocapsid Protein

ABSTRACT Human metapneumovirus (hMPV) has gained prominence in recent times as the predominant etiological agent of acute respiratory tract infections. This virus targets children, the elderly, and individuals with compromised immune systems. Given the protracted duration of hMPV transmission, it is probable that the majority of children will have acquired the virus by the age of 5. In individuals with compromised immune systems, recurrence of hMPV infection is possible. As hMPV matures, it remains latent from the time of acquisition. The genome of hMPV encompasses a pivotal protein referred to as the nucleocapsid protein (N). This protein assumes the form of a left‐handed helical nucleocapsid, enveloping the viral RNA genome. The primary function of this structure is to protect nucleases, rendering it a potentially promising target for therapeutic advancements. The present study employs a methodology that involves structure‐based virtual screening, followed by molecular dynamics simulation at a 250‐ns time scale, to identify potential natural molecules or their derivatives from the ZINC Database. These molecules are investigated for their binding properties against the hMPV nucleoprotein. Based on an evaluation of the docking score, binding site interaction, and molecular dynamics studies, it has been found that two naturally occurring molecules, namely M1 (ZINC85629735) and M3 (ZINC85569125), have shown notable docking scores of −9.6 and −10.7 kcal/mol, acceptable RMSD, RMSF, Rg, and so on calculated from molecular dynamics trajectory associated with MMGBSA binding energy of −81.94 and −99.63 kcal/mol, respectively. These molecules have shown the highest binding affinity toward nucleocapsid protein and demonstrated promising attributes as potential binders against hMPV.