Bioinformatics Institute, Agency for Science, Technology and Research (A∗STAR), Singapore 138671, Singapore; Department of Chemistry, Faculty of Science and Engineering, Manchester Institute of Biotechnology, The University of Manchester, Manchester M1 7DN, UK.
Bioinformatics Institute, Agency for Science, Technology and Research (A∗STAR), Singapore 138671, Singapore.
Structure. 2022 Aug 4;30(8):1062-1074.e4. doi: 10.1016/j.str.2022.05.006. Epub 2022 Jun 3.
The COVID-19 pandemic has prompted a rapid response in vaccine and drug development. Herein, we modeled a complete membrane-embedded SARS-CoV-2 spike glycoprotein and used molecular dynamics simulations with benzene probes designed to enhance discovery of cryptic pockets. This approach recapitulated lipid and host metabolite binding sites previously characterized by cryo-electron microscopy, revealing likely ligand entry routes, and uncovered a novel cryptic pocket with promising druggable properties located underneath the 617-628 loop. A full representation of glycan moieties was essential to accurately describe pocket dynamics. A multi-conformational behavior of the 617-628 loop in simulations was validated using hydrogen-deuterium exchange mass spectrometry experiments, supportive of opening and closing dynamics. The pocket is the site of multiple mutations associated with increased transmissibility found in SARS-CoV-2 variants of concern including Omicron. Collectively, this work highlights the utility of the benzene mapping approach in uncovering potential druggable sites on the surface of SARS-CoV-2 targets.
COVID-19 大流行促使疫苗和药物开发迅速响应。在此，我们构建了一个完整的膜嵌入 SARS-CoV-2 刺突糖蛋白，并使用苯探针进行分子动力学模拟，旨在增强对隐匿口袋的发现。这种方法再现了先前通过低温电子显微镜表征的脂质和宿主代谢物结合位点，揭示了可能的配体进入途径，并发现了一个位于 617-628 环下方的新隐匿口袋，具有有前途的可成药性。糖基部分的完整表示对于准确描述口袋动力学至关重要。使用氘氢交换质谱实验验证了模拟中 617-628 环的多构象行为，支持其打开和关闭动力学。该口袋是与传染性增加相关的多个突变的位点，在包括奥密克戎在内的 SARS-CoV-2 关注变体中都有发现。总的来说，这项工作强调了苯映射方法在揭示 SARS-CoV-2 靶标表面潜在可成药位点方面的效用。
