Near-physiological-temperature serial crystallography reveals conformations of SARS-CoV-2 main protease active site for improved drug repurposing

The COVID-19 pandemic has resulted in 198 million reported infections and more than 4 million deaths as of July 2021 (covid19.who.int). Research to identify effective therapies for COVID-19 includes: (1) designing a vaccine as future protection; (2) de novo drug discovery; and (3) identifying existi...

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Published in:	Structure (London) Vol. 29; no. 12; pp. 1382 - 1396.e6
Main Authors:	Durdagi, Serdar, Dağ, Çağdaş, Dogan, Berna, Yigin, Merve, Avsar, Timucin, Buyukdag, Cengizhan, Erol, Ismail, Ertem, Fatma Betul, Calis, Seyma, Yildirim, Gunseli, Orhan, Muge D., Guven, Omur, Aksoydan, Busecan, Destan, Ebru, Sahin, Kader, Besler, Sabri O., Oktay, Lalehan, Shafiei, Alaleh, Tolu, Ilayda, Ayan, Esra, Yuksel, Busra, Peksen, Ayse B., Gocenler, Oktay, Yucel, Ali D., Can, Ozgur, Ozabrahamyan, Serena, Olkan, Alpsu, Erdemoglu, Ece, Aksit, Fulya, Tanisali, Gokhan, Yefanov, Oleksandr M., Barty, Anton, Tolstikova, Alexandra, Ketawala, Gihan K., Botha, Sabine, Dao, E. Han, Hayes, Brandon, Liang, Mengning, Seaberg, Matthew H., Hunter, Mark S., Batyuk, Alex, Mariani, Valerio, Su, Zhen, Poitevin, Frederic, Yoon, Chun Hong, Kupitz, Christopher, Sierra, Raymond G., Snell, Edward H., DeMirci, Hasan
Format:	Journal Article
Language:	English
Published:	United States Elsevier Ltd 02-12-2021 Elsevier The Authors. Published by Elsevier Ltd
Subjects:	ambient temperature BASIC BIOLOGICAL SCIENCES Catalytic Domain Computer Simulation Coronavirus 3C Proteases - chemistry COVID-19 Drug Treatment Crystallography, X-Ray Dimerization Drug Design Drug Repositioning drug repurposing main protease Molecular Conformation Molecular Docking Simulation Principal Component Analysis Protein Conformation Recombinant Proteins - chemistry SARS-CoV-2 SFX Temperature ambient temperature SARS-CoV-2 drug repurposing SFX main protease
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Summary:	The COVID-19 pandemic has resulted in 198 million reported infections and more than 4 million deaths as of July 2021 (covid19.who.int). Research to identify effective therapies for COVID-19 includes: (1) designing a vaccine as future protection; (2) de novo drug discovery; and (3) identifying existing drugs to repurpose them as effective and immediate treatments. To assist in drug repurposing and design, we determine two apo structures of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease at ambient temperature by serial femtosecond X-ray crystallography. We employ detailed molecular simulations of selected known main protease inhibitors with the structures and compare binding modes and energies. The combined structural and molecular modeling studies not only reveal the dynamics of small molecules targeting the main protease but also provide invaluable opportunities for drug repurposing and structure-based drug design strategies against SARS-CoV-2. [Display omitted] •XFEL structures of SARS-CoV-2 Mpro reveal alternate drug-binding pocket conformations•Protomers of Mpro exhibit asymmetric behavior, as shown by MD simulations•Dimer interfaces in different space groups are stabilized by non-covalent interactions•Mpro interaction with non-covalent bound inhibitors results in unstable complexes Durdağı et al. represent radiation damage-free high-resolution SARS-CoV-2 main protease SFX structures obtained at near-physiological temperature and performed MD simulation of apo-form proteins and three known main protease inhibitors. The structures reveal alternate conformation, while MD simulation indicates asymmetric behavior of the protein, which is invaluable information for immediate drug-repurposing studies.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Bahcesehir University (BAU) Scientific Research Projects (BAP) AC02-76SF00515; NSF-1231306; 118C270; BAU2020-0101 National Science Foundation (NSF) Scientific and Technological Research Council of Turkey (TUBITAK) SLAC-PUB-17616 USDOE Office of Science (SC), Basic Energy Sciences (BES). Chemical Sciences, Geosciences & Biosciences Division Lead contact
ISSN:	0969-2126 1878-4186
DOI:	10.1016/j.str.2021.07.007