Bioinformatics approach for discovery of potential lead compound of NSP6 of SARS-CoV-2 using structure based virtual screening and molecular dynamics simulations.

Non-Structural Protein 6 (NSP6) is a crucial protein for SARS-CoV-2 as it performs a vital role in the replication and transcription of the virus. NSP6 plays a role in the stress response of the endoplasmic reticulum through binding to the sigma receptor 1 (SR1). Therefore, NSP6 is an interesting target for fighting SARS-CoV-2. The best model of the tertiary structure of NSP6 was predicted using the AlphaFold server, then this model was refined using the DeepRefiner server to construct a good-quality model. The current study utilized the virtual screening of the ZINC20 database for the identification of possible inhibitors using the computational docking Autodock Vina program and the post-docking analysis of energy calculations and interactions followed by ADMET studies which were widely used in potential hit identification and lead optimization. From the final hits, our study revealed the best eight compounds that have more potential to be considered as lead compounds for inhibition of a vital role of NSP6 in the replication and transcription of the virus with docking score and binding energy (E_score) with values ranging from - 49.64 to - 43.13 and all these compounds displayed no cellular cytotoxicity. These complexes in addition to the apoprotein were validated and analyzed using molecular dynamic simulations (MDS) for 100 ns. The NSP6-ZINC-141,457,420, NSP6-ZINC-075486396 complexes, revealed the highest complexes in H-bonds formation, NSP6-ZINC-018529632 complex was found to have the lowest binding energy score and NSP6-ZINC-089639800, NSP6-ZINC-157,610,683, NSP6-ZINC-075484852, NSP6-ZINC-016611776, and NSP6-ZINC-141,457,420 complexes presented no a significant deviation from the NSP6-apo protein in the Rg and SASA analysis and revealed promising performance in the RMSD and RMSF. This study exhibited that ZINC-141,457,420, ZINC-075486396, and ZINC-018529632 ligands have a promising potential for development as potential vaccines inhibiting SARS-CoV-2 NSP6 protein.