Towards the Identification of Novel Phytochemical Leads as Macrodomain Inhibitors of Chikungunya Virus Using Molecular Docking Approach

The outbreak of Chikungunya fever worldwide has raised a threat to human health and an economic burden on the affected countries. Currently, there is no cure for Chikungunya. The computational methods assist in identifying the drug leads for the target. This work reports the potential phytochemical inhibitors against a unique macro domain present in the conserved N-terminal region of Non- structural protein nsP3 of Chikungunya virus. Macro domain contributes a lot to viral fusion and replication. The shape based docking protocol was applied to predict the ligand conformations and their relative orientations with 2-ADP Ribose binding site of the target. The phytochemicals showed favorable bonded and non-bonded interactions with crucial amino acids. The binding affinity of the ligands to the target structure was estimated with six well- known scoring functions. An all- atom molecular dynamics simulation was performed for the macro domain in apo form and the complex with the best scoring ligand to study the stability and the conformational flexibility of the complexes. Based on the multiple scoring functions, drug- like properties, amino acid interactions and molecular dynamics studies, it is believed that the phytochemicals screened may well compete with the substrate. This is turn can inhibit the function of macro domain, eventually the loss of virulence of chikungunya virus. The work also gives a room for designing novel drugs using chemoinformatics, based on the structures of phytochemical leads reported in this study.