Computational Biological Center, IBM Thomas J. Watson Research, Yorktown Heights, New York 10598, USA.
Phys Chem Chem Phys. 2020 Nov 21;22(43):25335-25343. doi: 10.1039/d0cp03867a. Epub 2020 Nov 3.
Coronavirus disease 2019 (COVID-19) is an ongoing global pandemic with very limited specific treatments. To fight COVID-19, various traditional antiviral medicines have been prescribed in China to infected patients with mild to moderate symptoms and received unexpected success in controlling the disease. However, the molecular mechanisms of how these herbal medicines interact with the SARS-CoV-2 virus that causes COVID-19 have remained elusive. It is well known that the main protease (Mpro) of SARS-CoV-2 plays an important role in maturation of many viral proteins such as the RNA-dependent RNA polymerase. Here, we explore the underlying molecular mechanisms of the computationally determined top candidate, namely, rutin which is a key component in many traditional antiviral medicines such as Lianhuaqinwen and Shuanghuanlian, for inhibiting the viral target-Mpro. Using in silico methods (docking and molecular dynamics simulations), we revealed the dynamics and energetics of rutin when interacting with the Mpro of SARS-CoV-2, suggesting that the highly hydrophilic rutin molecule can be bound inside the Mpro's pocket (active site) and possibly inhibit its biological functions. In addition, we optimized the structure of rutin and designed two more hydrophobic analogs, M1 and M2, which satisfy the rule of five for western medicines and demonstrated that they (M2 in particular) possess much stronger binding affinities to the SARS-COV-2s Mpro than rutin, due to the enhanced hydrophobic interaction as well as more hydrogen bonds. Therefore, our results provide invaluable insights into the mechanism of a ligand's binding inside the Mpro and shed light on future structure-based designs of high-potent inhibitors for SARS-CoV-2 Mpro.
2019 年冠状病毒病（COVID-19）是一场持续的全球大流行，目前针对该疾病的特效疗法非常有限。为了对抗 COVID-19，中国给轻症和中度症状的感染患者开了各种传统的抗病毒药物，这些药物在控制疾病方面取得了意想不到的成功。然而，这些草药与导致 COVID-19 的 SARS-CoV-2 病毒相互作用的分子机制仍不清楚。众所周知，SARS-CoV-2 的主要蛋白酶（Mpro）在许多病毒蛋白（如 RNA 依赖性 RNA 聚合酶）的成熟过程中起着重要作用。在这里，我们探索了计算确定的候选药物芦丁的潜在分子机制，芦丁是许多传统抗病毒药物（如连花清瘟和双黄连）的关键成分，用于抑制病毒靶标-Mpro。我们使用计算方法（对接和分子动力学模拟）揭示了芦丁与 SARS-CoV-2 的 Mpro 相互作用时的动态和能量学，表明高度亲水的芦丁分子可以结合到 Mpro 的口袋（活性部位）内，并可能抑制其生物学功能。此外，我们对芦丁的结构进行了优化，并设计了另外两个更疏水的类似物 M1 和 M2，它们符合西药的五规则，并证明它们（特别是 M2）与芦丁相比，对 SARS-COV-2 的 Mpro 具有更强的结合亲和力，这是由于增强的疏水相互作用以及更多的氢键。因此，我们的研究结果为配体在 Mpro 内结合的机制提供了宝贵的见解，并为 SARS-CoV-2 Mpro 的基于结构的高潜力抑制剂的设计提供了新的思路。
