In-Silico targeting of SARS-CoV-2 NSP6 for drug and natural products repurposing.

ABSTRACT

Non-Structural Protein 6 (NSP6) has a protecting role for SARS-CoV-2 replication by inhibiting the expansion of autophagosomes inside the cell. NSP6 is involved in the endoplasmic reticulum stress response by binding to Sigma receptor 1 (SR1). Nevertheless, NSP6 crystal structure is not solved yet. Therefore, NSP6 is considered a challenging target in Structure-Based Drug Discovery. Herein, we utilized the high quality NSP6 model built by AlphaFold in our study. Targeting a putative NSP6 binding site is believed to inhibit the SR1-NSP6 protein-protein interactions. Three databases were virtually screened, namely FDA-approved drugs (DrugBank), Northern African Natural Products Database (NANPDB) and South African Natural Compounds Database (SANCDB) with a total of 8158 compounds. Further validation for 9 candidates via molecular dynamics simulations for 100 ns recommended potential binders to the NSP6 binding site. The proposed candidates are recommended for biological testing to cease the rapidly growing pandemic.