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 Ayan; Busra 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

doi:10.1016/j.str.2021.07.007

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 journal › Article › peer-review

23 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 language	English
Pages (from-to)	1382-1396.e6
Journal	Structure
Volume	29
Issue number	12
DOIs	https://doi.org/10.1016/j.str.2021.07.007
Publication status	Published - 2 Dec 2021
Externally published	Yes

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.

Funders	Funder number
James Fraser and Galen Correy
Max-Planck Institute for Medical Research
National Virtual Biotechnology Laboratory
Science and Technology Centers	NSF-1231306
TUBITAK	118C270
TUBITAK ULAKBIM
National Science Foundation
U.S. Department of Energy
Office of Science
Basic Energy Sciences	DE-AC02-76SF00515
SLAC National Accelerator Laboratory
Türkiye Bilimsel ve Teknolojik Araştirma Kurumu
Bahçeşehir Üniversitesi	BAU2020-0101

Keywords

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.str.2021.07.007

Cite this

Durdagi, S., Dağ, Ç., Dogan, B., Yigin, M., Avsar, T., Buyukdag, C., Erol, I., Ertem, F. B., Calis, S., Yildirim, G., Orhan, M. D., Guven, O., Aksoydan, B., Destan, E., Sahin, K., Besler, S. O., Oktay, L., Shafiei, A., Tolu, I., ... DeMirci, H. (2021). Near-physiological-temperature serial crystallography reveals conformations of SARS-CoV-2 main protease active site for improved drug repurposing. Structure, 29(12), 1382-1396.e6. https://doi.org/10.1016/j.str.2021.07.007

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

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.",

keywords = "SARS-CoV-2, SFX, ambient temperature, drug repurposing, main protease",

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

note = "Publisher Copyright: {\textcopyright} 2021 The Authors",

year = "2021",

month = dec,

day = "2",

doi = "10.1016/j.str.2021.07.007",

language = "English",

volume = "29",

pages = "1382--1396.e6",

journal = "Structure",

issn = "0969-2126",

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Durdagi, S, Dağ, Ç, Dogan, B, Yigin, M, Avsar, T, Buyukdag, C, Erol, I, Ertem, FB, Calis, S, Yildirim, G, Orhan, MD, Guven, O, Aksoydan, B, Destan, E, Sahin, K, Besler, SO, Oktay, L, Shafiei, A, Tolu, I, Ayan, E, Yuksel, B, Peksen, AB, Gocenler, O, Yucel, AD, Can, O, Ozabrahamyan, S, Olkan, A, Erdemoglu, E, Aksit, F, Tanisali, G, Yefanov, OM, Barty, A, Tolstikova, A, Ketawala, GK, Botha, S, Dao, EH, Hayes, B, Liang, M, Seaberg, MH, Hunter, MS, Batyuk, A, Mariani, V, Su, Z, Poitevin, F, Yoon, CH, Kupitz, C, Sierra, RG, Snell, EH & DeMirci, H 2021, 'Near-physiological-temperature serial crystallography reveals conformations of SARS-CoV-2 main protease active site for improved drug repurposing', Structure, vol. 29, no. 12, pp. 1382-1396.e6. https://doi.org/10.1016/j.str.2021.07.007

TY - JOUR

T1 - Near-physiological-temperature serial crystallography reveals conformations of SARS-CoV-2 main protease active site for improved drug repurposing

AU - Durdagi, Serdar

AU - Dağ, Çağdaş

AU - Dogan, Berna

AU - Yigin, Merve

AU - Avsar, Timucin

AU - Buyukdag, Cengizhan

AU - Erol, Ismail

AU - Ertem, Fatma Betul

AU - Calis, Seyma

AU - Yildirim, Gunseli

AU - Orhan, Muge D.

AU - Guven, Omur

AU - Aksoydan, Busecan

AU - Destan, Ebru

AU - Sahin, Kader

AU - Besler, Sabri O.

AU - Oktay, Lalehan

AU - Shafiei, Alaleh

AU - Tolu, Ilayda

AU - Ayan, Esra

AU - Yuksel, Busra

AU - Peksen, Ayse B.

AU - Gocenler, Oktay

AU - Yucel, Ali D.

AU - Can, Ozgur

AU - Ozabrahamyan, Serena

AU - Olkan, Alpsu

AU - Erdemoglu, Ece

AU - Aksit, Fulya

AU - Tanisali, Gokhan

AU - Yefanov, Oleksandr M.

AU - Barty, Anton

AU - Tolstikova, Alexandra

AU - Ketawala, Gihan K.

AU - Botha, Sabine

AU - Dao, E. Han

AU - Hayes, Brandon

AU - Liang, Mengning

AU - Seaberg, Matthew H.

AU - Hunter, Mark S.

AU - Batyuk, Alex

AU - Mariani, Valerio

AU - Su, Zhen

AU - Poitevin, Frederic

AU - Yoon, Chun Hong

AU - Kupitz, Christopher

AU - Sierra, Raymond G.

AU - Snell, Edward H.

AU - DeMirci, Hasan

PY - 2021/12/2

Y1 - 2021/12/2

N2 - 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.

AB - 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.

KW - SARS-CoV-2

KW - SFX

KW - ambient temperature

KW - drug repurposing

KW - main protease

UR - http://www.scopus.com/inward/record.url?scp=85112800022&partnerID=8YFLogxK

U2 - 10.1016/j.str.2021.07.007

DO - 10.1016/j.str.2021.07.007

M3 - Article

C2 - 34403647

AN - SCOPUS:85112800022

SN - 0969-2126

VL - 29

SP - 1382-1396.e6

JO - Structure

JF - Structure

IS - 12

ER -

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

Abstract

Bibliographical note

Funding

Keywords

UN SDGs

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