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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

By 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 Botha1, Gihan Kaushylal Ketawala1, Zhen Su, Brandon Hayes2, Frederic Poitevin, Alexander Batyuk, Chun Hong Yoon, Christopher Kupitz2, Serdar Durdagi, Raymond G. Sierra, Hasan Demirci3

1. Arizona State University 2. SLAC National Accelerator Laboratory 3. Biosciences Division at SLAC National Accelerator Laboratory

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BioXFEL Publications

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Type

journal-article

Author

Omur Guven and Mehmet Gul and Esra Ayan and J Austin Johnson and Baris Cakilkaya and Gozde Usta and Fatma Betul Ertem and Nurettin Tokay and Busra Yuksel and Oktay Gocenler and Cengizhan Buyukdag and Sabine Botha and Gihan Ketawala and Zhen Su and Brandon Hayes and Frederic Poitevin and Alexander Batyuk and Chun Hong Yoon and Christopher Kupitz and Serdar Durdagi and Raymond G. Sierra and Hasan DeMirci

Citation

Guven, O., Gul, M., Ayan, E., Johnson, J. A., Cakilkaya, B., Usta, G., Ertem, F. B., Tokay, N., Yuksel, B., Gocenler, O., Buyukdag, C., Botha, S., Ketawala, G., Su, Z., Hayes, B., Poitevin, F., Batyuk, A., Yoon, C. H., Kupitz, C., … DeMirci, H. (2021). Case Study of High-Throughput Drug Screening and Remote Data Collection for SARS-CoV-2 Main Protease by Using Serial Femtosecond X-ray Crystallography. Crystals, 11(12), 1579. https://doi.org/10.3390/cryst11121579

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 have 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 nine 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.

DOI

http://dx.doi.org/10.3390/cryst11121579