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Case Study of High-Throughput Drug Screening and Remote Data Collection for SARS-CoV-2 Main Protease by Using Serial Femtosecond X-ray Crystallography

View ORCID ProfileOmur Guven, View ORCID ProfileMehmet Gul, Esra Ayan, J. Austin Johnson, Baris Cakilkaya, Gozde Usta, View ORCID ProfileFatma Betul Ertem, View ORCID ProfileNurettin Tokay, View ORCID ProfileBusra Yuksel, View ORCID ProfileOktay Gocenler, View ORCID ProfileCengizhan Buyukdag, View ORCID ProfileSabine Botha, View ORCID ProfileGihan Ketawala, Zhen Su, Brandon Hayes, View ORCID ProfileFrederic Poitevin, Alexander Batyuk, Chun Hong Yoon, Christopher Kupitz, View ORCID ProfileSerdar Durdagi, View ORCID ProfileRaymond G. Sierra, View ORCID ProfileHasan DeMirci
doi: https://doi.org/10.1101/2021.11.28.468932
Omur Guven
1Department of Molecular Biology and Genetics, Koc University, 34450, Istanbul, Turkey
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Mehmet Gul
1Department of Molecular Biology and Genetics, Koc University, 34450, Istanbul, Turkey
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Esra Ayan
1Department of Molecular Biology and Genetics, Koc University, 34450, Istanbul, Turkey
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J. Austin Johnson
1Department of Molecular Biology and Genetics, Koc University, 34450, Istanbul, Turkey
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Baris Cakilkaya
1Department of Molecular Biology and Genetics, Koc University, 34450, Istanbul, Turkey
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Gozde Usta
1Department of Molecular Biology and Genetics, Koc University, 34450, Istanbul, Turkey
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Fatma Betul Ertem
1Department of Molecular Biology and Genetics, Koc University, 34450, Istanbul, Turkey
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Nurettin Tokay
1Department of Molecular Biology and Genetics, Koc University, 34450, Istanbul, Turkey
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Busra Yuksel
1Department of Molecular Biology and Genetics, Koc University, 34450, Istanbul, Turkey
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Oktay Gocenler
1Department of Molecular Biology and Genetics, Koc University, 34450, Istanbul, Turkey
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Cengizhan Buyukdag
1Department of Molecular Biology and Genetics, Koc University, 34450, Istanbul, Turkey
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Sabine Botha
2Department of Physics, Arizona State University, Tempe, AZ 85287-1504, USA
3Biodesign Center for Applied Structural Discovery, Arizona State University, Tempe, AZ 85287-5001, USA
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Gihan Ketawala
2Department of Physics, Arizona State University, Tempe, AZ 85287-1504, USA
3Biodesign Center for Applied Structural Discovery, Arizona State University, Tempe, AZ 85287-5001, USA
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Zhen Su
4Linac Coherent Light Source, SLAC National Accelerator Laboratory, 2575 Sand Hill Rd, Menlo Park, 94025, CA, USA
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Brandon Hayes
4Linac Coherent Light Source, SLAC National Accelerator Laboratory, 2575 Sand Hill Rd, Menlo Park, 94025, CA, USA
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Frederic Poitevin
4Linac Coherent Light Source, SLAC National Accelerator Laboratory, 2575 Sand Hill Rd, Menlo Park, 94025, CA, USA
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Alexander Batyuk
4Linac Coherent Light Source, SLAC National Accelerator Laboratory, 2575 Sand Hill Rd, Menlo Park, 94025, CA, USA
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Chun Hong Yoon
4Linac Coherent Light Source, SLAC National Accelerator Laboratory, 2575 Sand Hill Rd, Menlo Park, 94025, CA, USA
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Christopher Kupitz
4Linac Coherent Light Source, SLAC National Accelerator Laboratory, 2575 Sand Hill Rd, Menlo Park, 94025, CA, USA
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Serdar Durdagi
5Computational Biology and Molecular Simulations Laboratory, Department of Biophysics, School of Medicine, Bahcesehir University, Istanbul 34734, Turkey
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Raymond G. Sierra
4Linac Coherent Light Source, SLAC National Accelerator Laboratory, 2575 Sand Hill Rd, Menlo Park, 94025, CA, USA
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Hasan DeMirci
1Department of Molecular Biology and Genetics, Koc University, 34450, Istanbul, Turkey
6Koc University Isbank Center for Infectious Diseases (KUISCID), 34010, Istanbul, Turkey
7Stanford PULSE Institute, SLAC National Laboratory, Menlo Park, CA 94025, USA
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  • For correspondence: hdemirci@ku.edu.tr
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Abstract

Since early 2020, COVID-19 has grown to affect the lives of billions globally. A worldwide investigation has been ongoing for characterizing the virus and also for finding an effective drug and developing vaccines. As time has been of the essence, a crucial part of this research has been drug repurposing; therefore, confirmation of in-silico drug screening studies has been carried out for this purpose. Here we demonstrated the possibility of screening a variety of drugs efficiently by leveraging a high data collection rate of 120 images/second with the new low-noise, high dynamic range ePix10k2M Pixel Array Detector installed at the Macromolecular Femtosecond Crystallography (MFX) instrument at the Linac Coherent Light Source (LCLS). The X-ray Free-Electron Laser (XFEL) is used for remote high-throughput data collection for drug repurposing of the main protease (Mpro) of SARS-CoV-2 at ambient temperature with mitigated X-ray radiation damage. We obtained multiple structures soaked with 9 drug candidate molecules in two crystal forms. Although our drug binding attempts failed, we successfully established a high-throughput Serial Femtosecond X-ray crystallographic (SFX) data collection protocol.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted November 30, 2021.
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Case Study of High-Throughput Drug Screening and Remote Data Collection for SARS-CoV-2 Main Protease by Using Serial Femtosecond X-ray Crystallography
Omur Guven, Mehmet Gul, Esra Ayan, J. Austin Johnson, Baris Cakilkaya, Gozde Usta, Fatma Betul Ertem, Nurettin Tokay, Busra Yuksel, Oktay Gocenler, Cengizhan Buyukdag, Sabine Botha, Gihan Ketawala, Zhen Su, Brandon Hayes, Frederic Poitevin, Alexander Batyuk, Chun Hong Yoon, Christopher Kupitz, Serdar Durdagi, Raymond G. Sierra, Hasan DeMirci
bioRxiv 2021.11.28.468932; doi: https://doi.org/10.1101/2021.11.28.468932
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Case Study of High-Throughput Drug Screening and Remote Data Collection for SARS-CoV-2 Main Protease by Using Serial Femtosecond X-ray Crystallography
Omur Guven, Mehmet Gul, Esra Ayan, J. Austin Johnson, Baris Cakilkaya, Gozde Usta, Fatma Betul Ertem, Nurettin Tokay, Busra Yuksel, Oktay Gocenler, Cengizhan Buyukdag, Sabine Botha, Gihan Ketawala, Zhen Su, Brandon Hayes, Frederic Poitevin, Alexander Batyuk, Chun Hong Yoon, Christopher Kupitz, Serdar Durdagi, Raymond G. Sierra, Hasan DeMirci
bioRxiv 2021.11.28.468932; doi: https://doi.org/10.1101/2021.11.28.468932

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