Isatin-based virtual high throughput screening, molecular docking, DFT, QM/MM, MD and MM-PBSA study of novel inhibitors of SARS-CoV-2 main protease

Abstract

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a rapidly growing health care emergency across the world. One of the viral proteases called main protease or Mpro, plays a crucial role in the replication of SARS-CoV-2. As the structure of Mpro of SARS-CoV-2 is similar to the Mpro of SARS-CoV-1 (responsible for SARS outbreak between 2002 and 2004), we hypothesize that the inhibitors of SARS-CoV-1 Mpro can also inhibit the Mpro of SARS-CoV-2. To test this hypothesis, a total of 79 isatin derivatives, which inhibited Mpro activity under in vitro conditions, were selected from the literature, and then screened through AutoDock Vina. The chemical features of the top 5 isatin derivatives with low binding energies (−8.5 to −8.2 kcal/mol) were used to screen similar types of compounds from several small-molecule libraries containing 15856508 compounds. A total of 1,609 compounds with similarity score ≥ 6 were screened and then subjected to docking as well as ADME analysis. Among the compounds screened, 4 ligands form Zinc drug-like library (ZINC000008848565, ZINC000009513563, ZINC000036759789 and ZINC000046053855) showed good ADMET properties, low binding energy (−8.4 to −8.6 kcal/mol), low interaction energy (−72.62 to −50.01 kcal/mol) and high structural stability with Mpro. Hence, the selected ligands might serve as the lead candidates for further wet laboratory validation, optimization and development.

Communicated by Ramaswamy H. Sarma

Keywords:

• Coronavirus
• COVID-19
• SARS-CoV-2
• main protease
• screening
• molecular docking
• isatin

Acknowledgments

We duly acknowledge the use of super computing facility SCFBio, at the department of chemistry, Indian Institute of Technology, Delhi, India.

Disclosure statement

We declare no conflict of interest.

Author contributions

VV designed the study and wrote the manuscript. GSA, SS and VV analyzed and interpreted the results. All the authors approve the final version to be published.