Near-Physiological-Temperature Serial Crystallography Reveals Conformations of SARS-CoV-2 Main Protease Active Site for Improved Drug Repurposing. Durdagi et al

The COVID-19 pandemic has resulted in 185 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: i) designing a vaccine as future protection; ii) de novo drug discovery; and iii) 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.截至2021年7月，新型冠状病毒肺炎（COVID-19）全球累计报告感染病例达1.85亿例，死亡病例超400万例（数据来源：covid19.who.int）。针对COVID-19的有效治疗手段研究主要涵盖三大方向：其一，研发疫苗以提供未来防护；其二，全新药物发现（de novo drug discovery）；其三，筛选现有药物并将其重新定位为高效且可快速投入使用的治疗方案。为助力药物重定位与药物设计工作，本研究通过串行飞秒X射线晶体学（Serial Femtosecond X-ray crystallography）技术，解析了2个处于常温环境下的严重急性呼吸综合征冠状病毒2型（SARS-CoV-2）主蛋白酶（main protease）无配体结构（apo structure）。我们针对筛选得到的已知主蛋白酶抑制剂，结合上述解析的结构开展了精细化分子模拟，并对其结合模式与结合能进行了对比分析。本研究整合结构解析与分子建模相关成果，不仅揭示了靶向主蛋白酶的小分子化合物的动态行为特征，更为针对SARS-CoV-2的药物重定位以及基于结构的药物设计策略提供了极具价值的研究契机。