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Near-Physiological-Temperature Serial Femtosecond X-ray Crystallography Reveals Novel Conformations of SARS-CoV-2 Main Protease Active Site for Improved Drug Repurposing

By Serdar Durdagi, Cagdas Dag, Berna Dogan, Merve Yigin, Timucin Avsar, Cengizhan Buyukdag, Ismail Erol, 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 Kaushylal Ketawala1, Sabine Botha1, E. Han Dao, Brandon Hayes2, Mengning Liang, Matthew H. Seaberg, Mark S. Hunter2, Alex Batyuk, Valerio Mariani, Zhen Su, Frederic Poitevin, Chun Hong Yoon, Christopher Kupitz2, Raymond G. Sierra, Edward Snell3, Hasan Demirci4

1. Arizona State University 2. SLAC National Accelerator Laboratory 3. Hauptman-Woodward Medical Research Institute - SUNY Buffalo 4. Biosciences Division at SLAC National Accelerator Laboratory

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Category

BioXFEL Publications

Published on

Type

posted-content

Author

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

Citation

Durdagi, S. et al., 2020. Near-Physiological-Temperature Serial Femtosecond X-ray Crystallography Reveals Novel Conformations of SARS-CoV-2 Main Protease Active Site for Improved Drug Repurposing. Available at: http://dx.doi.org/10.1101/2020.09.09.287987.

Abstract

AbstractThe COVID19 pandemic has resulted in 25+ million reported infections and nearly 850.000 deaths. Research to identify effective therapies for COVID19 includes: i) designing a vaccine as future protection; ii) structure-based drug design; and iii) identifying existing drugs to repurpose them as effective and immediate treatments. To assist in drug repurposing and design, we determined two apo structures of Severe Acute Respiratory Syndrome CoronaVirus-2 main protease at ambienttemperature by Serial Femtosecond X-ray crystallography. We employed detailed molecular simulations of selected known main protease inhibitors with the structures and compared binding modes and energies. The combined structural biology and molecular modeling studies not only reveal the dynamics of small molecules targeting main protease but will also provide invaluable opportunities for drug repurposing and structure-based drug design studies against SARS-CoV-2.One Sentence SummaryRadiation-damage-free high-resolution SARS-CoV-2 main protease SFX structures obtained at near-physiological-temperature offer invaluable information for immediate drug-repurposing studies for the treatment of COVID19.

DOI

http://dx.doi.org/10.1101/2020.09.09.287987

Funding

NSF-STC Biology with X-ray Lasers (NSF-1231306)