Identification of a potential anti-viral drug targeting allosteric site of papain-like protease against rubella using a molecular modeling approach.

Rubella virus (RUBV) is responsible for causing rashes, lymphadenopathy, and fever which are the hallmarks of an acute viral illness called Rubella. For RUBV replication, the non-structural polyprotein p200 must be cleaved by the rubella papain-like protease (RubPro) into the multifunctional proteins p150 and p90. Hence, RubPro is an attractive target for anti-viral drug discovery. Moreover, the binding of host Calmodulin 1 (CaM) to RubPro modulates the protease activity and infectivity of RUBV. However, the binding mode of CaM and RubPro remain uncertain. Therefore, our investigation not only delves into understanding the interaction between CaM and the RubPro but also aims to recognize the allosteric site for the development of antiviral protease inhibitors. In this study, we interestingly identified the allosteric site in close vicinity with the CaM binding domain of RubPro. Considering the allosteric site of RubPro, we employed a computational modelling approach to identify the potential antiviral compounds. Leveraging ChemDiv protease inhibitors database, we employed structure-based virtual screening, ADME, pass prediction, and docking studies, unveiling three potent compounds: C073-2897, C073-3328, and C073-3368. Moreover, molecular dynamics simulation analysis revealed that these compounds affect the RubPro structure and dynamics and may also influence the binding of CaM with RubPro. Notably, binding energy calculation showed that the compound C073-3328 exhibits higher binding affinity, while C073-3368 displays a lower binding affinity with RubPro. These compounds signify potential for managing RUBV infections and pioneering effective antiviral treatments. This computational study could pave the way for improved methods of managing or controlling rubella infections.