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

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.

Authors:

Guven, Omur ^[1]; Gul, Mehmet  ^[1];

• Search DOE PAGES for author "Gul, Mehmet"
• Search DOE PAGES for ORCID "0000-0001-5513-1866"

Ayan, Esra ^[1]; Johnson, J. Austin ^[1]; Cakilkaya, Baris  ^[1];

• Search DOE PAGES for author "Cakilkaya, Baris"
• Search DOE PAGES for ORCID "0000-0001-6252-5943"

Usta, Gozde ^[1]; Ertem, Fatma Betul ^[1]; Tokay, Nurettin ^[1]; Yuksel, Busra  ^[1];

• Search DOE PAGES for author "Yuksel, Busra"
• Search DOE PAGES for ORCID "0000-0003-4396-7142"

Gocenler, Oktay ^[1]; Buyukdag, Cengizhan ^[1]; Botha, Sabine ^[2]; Ketawala, Gihan ^[2]; Su, Zhen ^[3]; Hayes, Brandon ^[4]; Poitevin, Frederic ^[4]; Batyuk, Alexander ^[4]; Yoon, Chun Hong ^[4]; Kupitz, Christopher  ^[4];

• Search DOE PAGES for author "Kupitz, Christopher"
• Search DOE PAGES for ORCID "0000-0002-7940-3042"

Durdagi, Serdar  ^[5]

• Search DOE PAGES for author "Durdagi, Serdar"
• Search DOE PAGES for ORCID "0000-0002-0426-0905"

more »; Sierra, Raymond G. ^[4]; DeMirci, Hasan  ^[6]

• Search DOE PAGES for author "DeMirci, Hasan"
• Search DOE PAGES for ORCID "0000-0002-9135-5397"

« less

---

+ Show Author Affiliations

1. Koc Univ., Istanbul (Turkey)
2. Arizona State Univ., Tempe, AZ (United States)
3. SLAC National Accelerator Lab., Menlo Park, CA (United States); Stanford Univ., CA (United States)
4. SLAC National Accelerator Lab., Menlo Park, CA (United States)
5. Bahcesehir Univ., Istanbul (Turkey)
6. Koc Univ., Istanbul (Turkey); SLAC National Accelerator Lab., Menlo Park, CA (United States)

Publication Date:

Fri Dec 17 00:00:00 EST 2021

Research Org.:

SLAC National Accelerator Lab., Menlo Park, CA (United States)

Sponsoring Org.:

USDOE Office of Science (SC), Basic Energy Sciences (BES); National Science Foundation (NSF) Science and Technology Centers

OSTI Identifier:

1878584

Alternate Identifier(s):

OSTI ID: 1877674

Grant/Contract Number:  

AC02-76SF00515; NSF-1231306

Resource Type:

Accepted Manuscript

Journal Name:

Crystals

Additional Journal Information:

Journal Volume: 11; Journal Issue: 12; Journal ID: ISSN 2073-4352

Publisher:

MDPI

Country of Publication:

United States

Language:

English

Subject:

60 APPLIED LIFE SCIENCES; SARS-CoV-2; main protease; serial femtosecond crystallography; high-throughput drug screening