Chemical-informatics approach to COVID-19 drug discovery: Exploration of important fragments and data mining based prediction of some hits from natural origins as main protease (Mpro) inhibitors

• Published in: Journal of molecular structure 2021-01, Vol.1224, p.129026-129026, Article 129026
• Main Authors: Ghosh, Kalyan, Amin, Sk. Abdul, Gayen, Shovanlal, Jha, Tarun
• Format: Article
• Language: English
• Subjects: COVID-19; Monte Carlo based optimization; Natural product; SARS-CoV Mpro; SARS-CoV-2; SPCI analysis
• ISSN: 0022-2860; 1872-8014
• DOI: 10.1016/j.molstruc.2020.129026

•It is challenging to identify effective SARS-CoV-2 main protease inhibitor urgently.•This study involves classification QSAR based data mining of diverse SARS-CoV Mpro inhibitors.•Important molecular features regulating the Mpro inhibitory properties are identified.•Prediction of recently reported natural origin based virtual hits is reported. As the world struggles against current global pandemic of novel coronavirus disease (COVID-19), it is challenging to trigger drug discovery efforts to search broad-spectrum antiviral agents. Thus, there is a need of strong and sustainable global collaborative works especially in terms of new and existing data analysis and sharing which will join the dots of knowledge gap. Our present chemical-informatics based data analysis approach is an attempt of application of previous activity data of SARS-CoV main protease (Mpro) inhibitors to accelerate the search of present SARS-CoV-2 Mpro inhibitors. The study design was composed of three major aspects: (1) classification QSAR based data mining of diverse SARS-CoV Mpro inhibitors, (2) identification of favourable and/or unfavourable molecular features/fingerprints/substructures regulating the Mpro inhibitory properties, (3) data mining based prediction to validate recently reported virtual hits from natural origin against SARS-CoV-2 Mpro enzyme. Our Structural and physico-chemical interpretation (SPCI) analysis suggested that heterocyclic nucleus like diazole, furan and pyridine have clear positive contribution while, thiophen, thiazole and pyrimidine may exhibit negative contribution to the SARS-CoV Mpro inhibition. Several Monte Carlo optimization based QSAR models were developed and the best model was used for screening of some natural product hits from recent publications. The resulted active molecules were analysed further from the aspects of fragment analysis. This approach set a stage for fragment exploration and QSAR based screening of active molecules against putative SARS-CoV-2 Mpro enzyme. We believe the future in vitro and in vivo studies would provide more perspectives for anti-SARS-CoV-2 agents.