Potential Alphavirus Inhibitors From Phytocompounds – Molecular Docking and Dynamics Based Approach

Abstract

Background. Alphaviral diseases are an economic burden all over the world due to their chronicity and distribution worldwide. The glycoproteins E1 and E2 are important for binding to the surface of the host cell by interacting with the receptors and non-structural proteins named nsP2 and nsP4 are important for the replication of virus, so can be an important drug discovery target. Objective. We are aimed to explore the in silico interaction between plant-based compounds (phytocompounds) and specific protein targets, such as nonstructural protein nsP4 and glycoprotein E2 of Sindbis virus (SINV), nsP2 and E2 of Chikungunya virus (CHIKV), and glycoproteins E1 and E2 of Ross River virus (RRV). Methods. A library of phytochemicals from Indian medicinal plants was prepared using databases and converted to 3D structures. Protein structures (nsP2, nsp4, E1, E2) were obtained and refined, followed by molecular docking with AutoDock Vina. Promising ligands were evaluated for properties, cytotoxicity, and mutagenicity, considering drug-likeness and potential issues. Molecular Dynamics simulations assessed complex stability. Results. We analyzed 375 phytocompounds against these targets using molecular docking, modeling, and molecular dynamics for SINV, CHIKV, and Ross River (RRV) virus proteins. Granatin A has been found to successfully bind to the target sites of SINV nsP4, CHIKV E2, and CHIKV nsP2 with binding affinity values of -16.2, -20.6, and -18.6 Kcal/mol respectively. Further, stability of CHIKV E2 – Granatin A complex was done by performing molecular dynamic simulation and the complex was stable at 60ps. Conclusions. This research provides valuable insights into the development of effective antiviral drugs against alphaviruses, emphasizing the importance of natural compounds and their interactions with viral proteins. This study might pave the way for further exploration of these small molecules as effective anti-alphaviral therapeutic agents.