SARS-CoV M^pro inhibitory activity of aromatic disulfide compounds: QSAR model

The main protease (M^pro) of SARS-associated coronavirus (SARS-CoV) had caused a high rate of mortality in 2003. Current events (2019–2020) substantiate important challenges for society due to coronaviruses. Consequently, advancing models for the antiviral activity of therapeutic agents is a necessary component of the fast development of treatment for the virus. An analogy between anti-SARS agents suggested in 2017 and anti-coronavirus COVID-19 agents are quite probable. Quantitative structure-activity relationships for SARS-CoV are developed and proposed in this study. The statistical quality of these models is quite good. Mechanistic interpretation of developed models is based on the statistical and probability quality of molecular alerts extracted from SMILES. The novel, designed structures of molecules able to possess anti-SARS activities are suggested. For the final assessment of the designed molecules inhibitory potential, developed from the obtained QSAR model, molecular docking studies were applied. Results obtained from molecular docking studies were in a good correlation with the results obtained from QSAR modeling. Communicated by Ramaswamy H. Sarma

2003年，严重急性呼吸综合征冠状病毒（SARS-associated coronavirus, SARS-CoV）的主要蛋白酶（main protease, Mpro）曾导致极高的患者死亡率。2019至2020年暴发的新冠疫情进一步印证了冠状病毒对人类社会的严峻挑战。因此，构建治疗药物抗病毒活性预测模型，是加快该病毒治疗手段研发的必要环节。2017年提出的抗SARS治疗药物与抗新型冠状病毒肺炎（coronavirus disease 2019, COVID-19）治疗药物之间具备较高的类比可行性。本研究构建并提出了针对SARS-CoV的定量构效关系（quantitative structure-activity relationships, QSAR）模型，该模型具备优异的统计性能。所构建模型的机理解释，基于从简化分子线性输入规范（Simplified Molecular Input Line Entry System, SMILES）中提取的分子警示的统计与概率特性。本研究同时提出了一系列具备抗SARS活性潜力的全新分子设计结构。为最终评估基于所得QSAR模型设计的分子的抑制活性，本研究开展了分子对接（molecular docking）实验。分子对接实验所得结果与QSAR建模结果呈现出良好的相关性。本文由Ramaswamy H. Sarma通讯。