First report on the QSAR modelling and multistep virtual screening of the inhibitors of nonstructural protein Nsp14 of SARS-CoV-2: Reducing unnecessary chemical synthesis and experimental tests

[Display omitted] •The QSAR model for the inhibitors of SARS-CoV-2 Nsp14 was built for the first time.•Mechanistic analysis identified the main influencing factors for Nsp14 inhibition.•The best model was used for virtual screening of 262 untested compounds.•Docking and ADMET predictions identified two hit candidates as Nsp14 inhibitors.•The developed QSAR model can avoid unnecessary chemical synthesis and test. Corona Virus Disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), poses a serious threat to human health and life safety. How to effectively prevent and treat COVID-19 is crucial. In this study, we used the inhibitors of nonstructural protein Nsp14 of SARS-CoV-2 to perform the quantitative structure activity relationship (QSAR) modelling for the first time. Based on different dataset division strategies, we selected partial least square (PLS) and multiple linear regression (MLR) methods to develop easily interpretable and reproducible QSAR models with 2D molecular descriptors. All models complied with the strict QSAR validation principles of OECD and internationally recognized validation metrics. The best model contained two molecular descriptors with the following statistical parameters: R2 = 0.7796, QLOO2= 0.7373, Rtest2 = 0.8539 and CCCtest = 0.9073. Obviously, the model exhibited good prediction performance and can be used for quickly predicting the inhibitory activity of unknown compounds against Nsp14. Mechanistic interpretation identified the detailed relationship between molecular structure information and inhibitory activity. The best QSAR model was used to predict the inhibitory activity of 263 true external compounds without experimental values against Nsp14, and the prediction reliability was analyzed and discussed. Molecular docking and ADMET analyses were conducted for compounds with higher similarity to the modelling compounds. Finally, two compounds were identified as potential candidate drugs of targeting Nsp14. The current work lays a solid theoretical foundation for the discovery of inhibitors targeting Nsp14, and has an important reference significance for the development of anti-COVID-19 drugs.