Fragment-based in silico design of SARS-CoV-2 main protease inhibitors

Ahmad, Sarfraz and Mirza, Muhammad Usman and Kee, Lee Yean and Nazir, Mamoona and Abdul Rahman, Noorsaadah and Trant, John F. and Abdullah, Iskandar (2021) Fragment-based in silico design of SARS-CoV-2 main protease inhibitors. Chemical Biology & Drug Design, 98 (4). pp. 604-619. ISSN 1747-0277, DOI

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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 7,158 stereoisomers were screened using Glide (standard precision and extra precision), AutoDock Vina, and Prime MMGBSA. The top 22 hits having conformations approaching the linear combination of their constituent fragments were selected for MD simulation on Desmond. MD simulation suggested 15 of these did adopt conformations very close to their constituent pieces with far higher binding affinity than either constituent domain alone. These structures could provide a starting point for the further design of SARS-CoV-2 3CLpro inhibitors with improved binding, and structures are provided.

Item Type: Article
Funders: Universiti Malaya (IIRG003A-2019), Natural Sciences and Engineering Research Council of Canada (NSERC) CGIAR (553704-20)
Uncontrolled Keywords: Coronavirus COVID-19; Fragment-based drug discovery; Main protease Mpro 3CLpro; Multivalency; SARS-CoV-2; X-ray crystal structure
Subjects: Q Science > QD Chemistry
Q Science > QH Natural history > QH301 Biology
R Medicine > RM Therapeutics. Pharmacology
R Medicine > RS Pharmacy and materia medica
Divisions: Faculty of Science > Department of Chemistry
Depositing User: Ms Zaharah Ramly
Date Deposited: 12 Apr 2022 04:56
Last Modified: 12 Apr 2022 04:56

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