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

Serdar Durdagi*, Çağdaş Dağ, Berna Dogan, Merve Yigin, Timucin Avsar, Cengizhan Buyukdag, Ismail Erol, Fatma Betul Ertem, Seyma Calis, Gunseli Yildirim, Muge D. Orhan, Omur Guven, Busecan Aksoydan, Ebru Destan, Kader Sahin, Sabri O. Besler, Lalehan Oktay, Alaleh Shafiei, Ilayda Tolu, Esra AyanBusra Yuksel, Ayse B. Peksen, Oktay Gocenler, Ali D. Yucel, Ozgur Can, Serena Ozabrahamyan, Alpsu Olkan, Ece Erdemoglu, Fulya Aksit, Gokhan Tanisali, Oleksandr M. Yefanov, Anton Barty, Alexandra Tolstikova, Gihan K. Ketawala, Sabine Botha, E. Han Dao, Brandon Hayes, Mengning Liang, Matthew H. Seaberg, Mark S. Hunter, Alex Batyuk, Valerio Mariani, Zhen Su, Frederic Poitevin, Chun Hong Yoon, Christopher Kupitz, Raymond G. Sierra, Edward H. Snell, Hasan DeMirci*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

19 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1382-1396.e6
JournalStructure
Volume29
Issue number12
DOIs
Publication statusPublished - 2 Dec 2021
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2021 The Authors

Funding

Authors would like to dedicate this manuscript to the memory of John C. H. Spence. H.D. acknowledges support from National Science Foundation (NSF) Science and Technology Centers grant NSF-1231306 (Biology with X-ray Lasers, BioXFEL) and The Scientific and Technological Research Council of Turkey (TUBITAK) grant ( 118C270 ). H.D. would like to thank Michelle Young, Ritu Khurana, Lori Anne Love, and Tracy Chou for their invaluable support and discussions. The authors would like to thank James Fraser and Galen Correy for their critical reading of our manuscript and their comments. Use of the Linac Coherent Light Source (LCLS), SLAC National Accelerator Laboratory, is supported by the U.S. Department of Energy , Office of Science, Office of Basic Energy Sciences under contract no. DE-AC02-76SF00515 . The HERA system for in helium experiments at MFX was developed by Bruce Doak and funded by the Max-Planck Institute for Medical Research . Research was supported by the DOE Office of Science through the National Virtual Biotechnology Laboratory, a consortium of DOE national laboratories focused on response to COVID-19, with funding provided by the Coronavirus CARES Act. The numerical calculations reported in this paper were partially performed at TUBITAK ULAKBIM, High Performance and Grid Computing Center (TRUBA resources). S.D. and I.E. acknowledge TRUBA for the computational resources. S.D. acknowledges support from Bahcesehir University (BAU) Scientific Research Projects (BAP) grant ( BAU2020-0101 ). Authors would like to dedicate this manuscript to the memory of John C. H. Spence. H.D. acknowledges support from National Science Foundation (NSF) Science and Technology Centers grant NSF-1231306 (Biology with X-ray Lasers, BioXFEL) and The Scientific and Technological Research Council of Turkey (TUBITAK) grant (118C270). H.D. would like to thank Michelle Young, Ritu Khurana, Lori Anne Love, and Tracy Chou for their invaluable support and discussions. The authors would like to thank James Fraser and Galen Correy for their critical reading of our manuscript and their comments. Use of the Linac Coherent Light Source (LCLS), SLAC National Accelerator Laboratory, is supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences under contract no. DE-AC02-76SF00515. The HERA system for in helium experiments at MFX was developed by Bruce Doak and funded by the Max-Planck Institute for Medical Research. Research was supported by the DOE Office of Science through the National Virtual Biotechnology Laboratory, a consortium of DOE national laboratories focused on response to COVID-19, with funding provided by the Coronavirus CARES Act. The numerical calculations reported in this paper were partially performed at TUBITAK ULAKBIM, High Performance and Grid Computing Center (TRUBA resources). S.D. and I.E. acknowledge TRUBA for the computational resources. S.D. acknowledges support from Bahcesehir University (BAU) Scientific Research Projects (BAP) grant (BAU2020-0101). H.D. and S.D. designed and coordinated the project. H.D. C.D. M.Y. C.B. F.B.E. G.Y. O.G. S.O.B. A.S. F.A. and G.T. prepared the samples. B.H. M.L. M.H.S. M.S.H. A.B. V.M. Z.S. F.P. C.H.Y. C.K. and R.G.S. performed the sample delivery and on-site data collection. H.D. C.D. B.D. M.Y. C.B. I.E. F.B.E. S.C. G.Y. M.D.O. O.G. E.D. S.O.B. A.S. E.A. B.Y. A.B.P. O.G. A.D.Y. O.C. S.O. and E.H.D. performed the remote data collection. S.B. O.M.Y. A.B. A.T. G.K.K. Z.S. F.P. and C.H.Y. executed the data processing and reduction. S.D. B.D. T.A. I.E. S.C. M.D.O. B.A. K.S. L.O. I.T. A.O. and E.E. performed the in silico analysis. Structures were refined by H.D. Data were analyzed by H.D. E.S. S.D. C.D. E.D. B.Y. I.E. B.D. and T.A. The manuscript was prepared by H.D. and S.D. with input from all the coauthors. The authors declare no competing interests.

FundersFunder number
James Fraser and Galen Correy
Max-Planck Institute for Medical Research
National Virtual Biotechnology Laboratory
Science and Technology CentersNSF-1231306
TUBITAK118C270
TUBITAK ULAKBIM
National Science Foundation
U.S. Department of Energy
Office of Science
Basic Energy SciencesDE-AC02-76SF00515
SLAC National Accelerator Laboratory
Türkiye Bilimsel ve Teknolojik Araştirma Kurumu
Bahçeşehir ÜniversitesiBAU2020-0101

    Keywords

    • SARS-CoV-2
    • SFX
    • ambient temperature
    • drug repurposing
    • main protease

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