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

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

Structure (London, England : 1993) (2021-08-18)

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

PMID34403647

초록

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.