In silico investigation of potential small molecule inhibitors of the SARS-CoV-2 nsp10-nsp16 methyltransferase complex

Highlights: • The SARS-CoV-2 nsp10-nsp16 methyltransferase is required for viral RNA stability. • Initial screen of 300 small molecules to nsp16 S-adenosylmethionine-binding site. • In-depth molecular docking study of top 30 compounds based on initial screen. • Six lead compounds including lopinavir/ritonavir and cyanidin glucoside identified. • MD simulations reveal oleuropein as a potential methyltransferase inhibitor. The COVID-19 pandemic caused by SARS-CoV-2 has resulted in an international health emergency. The SARS-CoV-2 nsp16 is an S-adenosyl-L-methionine (SAM)-dependent methyltransferase, and with its cofactor nsp10, is responsible for RNA cap formation. This study aimed to identify small molecules binding to the SAM-binding site of the nsp10-nsp16 heterodimer for potential inhibition of methyltransferase activity. By screening a library of 300 compounds, 30 compounds were selected based on binding scores, side-effects, and availability. Following more advanced docking, six potential lead compounds were further investigated using molecular dynamics simulations. This revealed the dietary compound oleuropein as a potential methyltransferase inhibitor.