Enzymatic reaction molecular dynamics simulations for covalent inhibitors of SARS-CoV-2 main protease

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K04993
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 32010:Fundamental physical chemistry-related
• Research Institution: Waseda University (2022-2023); Kyoto University (2021)
• Principal Investigator: Ono Junichi 早稲田大学, 理工学術院総合研究所(理工学研究所), 次席研究員 (30777991)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: 新型コロナウイルス / COVID-19 / SARS-CoV-2 / メインプロテアーゼ / 共有結合阻害剤 / 量子分子動力学法 / 自由エネルギー解析 / インシリコ創薬

Outline of Final Research Achievements

Focusing on the main protease (Mpro) of SARS-CoV-2, the virus responsible for COVID-19 symptoms, microscopic mechanisms of covalent bond formation between Mpro and its ligands involving proton transfers and nucleophilic substitution reactions were theoretically elucidated using large-scale quantum molecular dynamics (MD) simulations coupled with an enhanced sampling method. In addition, Hybrid in silico drug discovery was performed by combining large-scale quantum MD simulations with the conventional in silico drug discovery, i.e., virtual screening and docking, with a focus on developing potent covalent inhibitors against Mpro. As a result, a promising candidate compound with high binding affinity and binding reactivity relative to approved oral drugs was identified.

Free Research Field

基礎物理化学

Academic Significance and Societal Importance of the Research Achievements

本研究では，量子分子動力学（MD）法と拡張サンプリング法を併用することにより，SARS-CoV-2メインプロテアーゼ（Mpro）と基質あるいは阻害剤分子とのプロトン移動を伴う共有結合形成過程の反応機構を解明した．また，従来型in silico創薬と量子MD法とを組み合わせたハイブリッド型in silico創薬によって，高い結合親和性と反応性を有する共有結合性の新規候補化合物を見出した．本手法は，Mproのみならず，例えば発がん性RASタンパク質のような結合部位に反応性の高いアミノ酸残基を持つ創薬標的タンパク質全般に対して有用であると期待される．以上より，本研究の学術的・社会的意義は十分に高い．