Development of a simple, interpretable and easily transferable QSAR model for quick screening antiviral databases in search of novel 3C-like protease (3CLpro) enzyme inhibitors against SARS-CoV diseases V. Kumar and K. Roy Drug Theoretics and Cheminformatics Laboratory, Department of Pharmaceutical Technology, Jadavpur University, Kolkata, India ABSTRACT In the context of recently emerged pandemic of COVID-19, we have performed two-dimensional quantitative structure-activity relation- ship (2D-QSAR) modelling using SARS-CoV-3CLpro enzyme inhibi- tors for the development of a multiple linear regression (MLR) based model. We have used 2D descriptors with an aim to develop an easily interpretable, transferable and reproducible model which may be used for quick prediction of SAR-CoV-3CLpro inhibitory activity for query compounds in the screening process. Based on the insights obtained from the developed 2D-QSAR model, we have identifed the structural features responsible for the enhancement of the inhibitory activity against 3CLpro enzyme. Moreover, we have performed the molecular docking analysis using the most and least active molecules from the dataset to understand the molecular interactions involved in binding, and the results were then correlated with the essential structural features obtained from the 2D-QSAR model. Additionally, we have performed in silico predictions of SARS-CoV 3CLpro enzyme inhibitory activity of a total of 50,437 compounds obtained from two anti-viral drug databases (CAS COVID-19 antiviral candidate compound database and another recently reported list of prioritized compounds from the ZINC15 database) using the developed model and provided prioritized compounds for experimental detection of their perfor- mance for SARS-CoV 3CLpro enzyme inhibition. ARTICLE HISTORY Received 30 April 2020 Accepted 27 May 2020 KEYWORDS 2D-QSAR; MLR; 3CLpro enzyme; SARS-CoV-2; Covid- 19; docking and virtual screening Introduction Severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) is a positive-sense single stranded RNA virus, informally known as the corona virus [1,2]. The virus was frst identifed in Wuhan, China by the Centres for Disease Control and Prevention (CDC) in the year of 2019 [2,3]. Since then, the virus has spread to others countries by infected people, and now this is a threat to global health [3,4].The virus spreads from person to person through close contact with someone who has the infection [5]. The disease is most infectious when a person is symptomatic [6]. However it is possible for someone without CONTACT K. Roy kunal.roy@jadavpuruniversity.in Supplemental data for this article can be accessed at: https://doi.org/10.1080/1062936X.2020.1776388. SAR AND QSAR IN ENVIRONMENTAL RESEARCH 2020, VOL. 31, NO. 7, 511–526 https://doi.org/10.1080/1062936X.2020.1776388 © 2020 Informa UK Limited, trading as Taylor & Francis Group