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Novel Inhibitors of 2′-O-Methyltransferase of the SARS-CoV-2 Coronavirus
Authors:Alexey Sulimov  Danil Kutov  Ivan Ilin  Yibei Xiao  Sheng Jiang  Vladimir Sulimov
Affiliation:1.Research Computing Center, Lomonosov Moscow State University, 119992 Moscow, Russia; (A.S.); (I.I.);2.School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China; (Y.X.); (S.J.)
Abstract:The COVID-19 pandemic is still affecting many people worldwide and causing a heavy burden to global health. To eliminate the disease, SARS-CoV-2, the virus responsible for the pandemic, can be targeted in several ways. One of them is to inhibit the 2′-O-methyltransferase (nsp16) enzyme that is crucial for effective translation of viral RNA and virus replication. For methylation of substrates, nsp16 utilizes S-adenosyl methionine (SAM). Binding of a small molecule in the protein site where SAM binds can disrupt the synthesis of viral proteins and, as a result, the replication of the virus. Here, we performed high-throughput docking into the SAM-binding site of nsp16 for almost 40 thousand structures, prepared for compounds from three libraries: Enamine Coronavirus Library, Enamine Nucleoside Mimetics Library, and Chemdiv Nucleoside Analogue Library. For the top scoring ligands, semi-empirical quantum-chemical calculations were performed, to better estimate protein–ligand binding enthalpy. Relying upon the calculated binding energies and predicted docking poses, we selected 21 compounds for experimental testing.
Keywords:SARS-CoV-2   nsp16 inhibitor   docking   quantum chemistry   virtual screening
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