Institute of Applied Mathematics (IUMA), Universidad de Zaragoza, Pedro Cerbuna 12, E-50009 Zaragoza, Spain and ARAID Foundation, Government of Aragón, 50018 Zaragoza, Spain.
Chaos. 2020 Jun;30(6):061102. doi: 10.1063/5.0013029.
There is an urgent necessity of effective medication against severe acute respiratory syndrome coronavirus 2 (SARS CoV-2), which is producing the COVID-19 pandemic across the world. Its main protease (M) represents an attractive pharmacological target due to its involvement in essential viral functions. The crystal structure of free M shows a large structural resemblance with the main protease of SARS CoV (nowadays known as SARS CoV-1). Here, we report that average SARS CoV-2 M is 1900% more sensitive than SARS CoV-1 M in transmitting tiny structural changes across the whole protein through long-range interactions. The largest sensitivity of M to structural perturbations is located exactly around the catalytic site Cys-145 and coincides with the binding site of strong inhibitors. These findings, based on a simplified representation of the protein as a residue network, may help in designing potent inhibitors of SARS CoV-2 M.
目前全球正爆发由严重急性呼吸系统综合征冠状病毒 2（SARS-CoV-2）引发的 COVID-19 疫情，我们急需有效的药物来对抗这种病毒。其主蛋白酶（M）在病毒的关键功能中发挥着重要作用，是一种极具吸引力的药物靶点。游离主蛋白酶 M 的晶体结构与严重急性呼吸系统综合征冠状病毒（如今称为 SARS-CoV-1）的主蛋白酶高度相似。在此，我们报告称，普通 SARS-CoV-2 的主蛋白酶 M 对结构变化的敏感性比 SARS-CoV-1 主蛋白酶 M 高 1900%，这是因为 SARS-CoV-2 主蛋白酶 M 能够通过长程相互作用在整个蛋白质中传递微小的结构变化。M 对结构干扰的最大敏感性恰好位于催化位点半胱氨酸 145 周围，且与强效抑制剂的结合位点相吻合。这些发现基于对蛋白质残基网络的简化表示，可以帮助设计 SARS-CoV-2 主蛋白酶 M 的强效抑制剂。
