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Fragment-Based In Silico Design Of Sars-Cov-2 Main Protease Inhibitors, Sarfraz Ahmad, Muhammad Usman Mirza, Lee Yean Kee, Mamoona Nazir, Noorsaadah Abd Rahman, John F. Trant, Iskandar Abdullah

Chemistry and Biochemistry Publications

3CLpro is essential for SARS-CoV-2 replication and infection; its inhibition using small molecules is a potential therapeutic strategy. In this study, a comprehensive crystallography-guided fragment-based drug discovery approach was employed to design new inhibitors for SARS-CoV-2 3CLpro. All small molecules co-crystallized with SARS-CoV-2 3CLpro with structures deposited in the Protein Data Bank were used as inputs. Fragments sitting in the binding pocket (87) were grouped into eight geographical types. They were interactively coupled using various synthetically reasonable linkers to generate larger molecules with divalent binding modes taking advantage of two different fragments' interactions. In total, 1,251 compounds were proposed, and …