Dynamic Profiling of β-Coronavirus 3CL Mpro Protease Ligand-Binding Sites

• DOI: 10.1021/acs.jcim.1c00449
• Publication Date: 2021-06-14T15:19:30Z
• Authors: Eunice Cho; Margarida Rosa; Ruhi Anjum; Saman Mehmood; Mariya Soban; Moniza Mujtaba; Khair Bux; Syed T. Moin; Mohammad Tanweer; Sarath Dantu; Alessandro Pandini; Junqi Yin; Heng Ma; Arvind Ramanathan; Barira Islam; Antonia S. J. S. Mey; Debsindhu Bhowmik; Shozeb Haider
• Keywords: Coronavirus

β-coronavirus (CoVs) alone has been responsible for three major global outbreaks in the 21st century. The current crisis led to an urgent requirement develop therapeutics. Even though a number of vaccines are available, alternative strategies targeting essential viral components required as backup against emergence lethal variants. One such target is main protease (Mpro) that plays indispensable role replication. availability over 270 Mpro X-ray structures complex with inhibitors provides unique insights into ligand-protein interactions. Herein, we provide comprehensive comparison all nonredundant ligand-binding sites available SARS-CoV2, SARS-CoV, and MERS-CoV Mpro. Extensive adaptive sampling used investigate structural conservation using Markov state models (MSMs) compare conformational dynamics employing convolutional variational auto-encoder-based deep learning. Our results indicate not dynamically conserved despite high sequence across β-CoV homologs. This highlights complexity enzymes single pan inhibitor.