Protein degradation: a novel computational approach to design protein degrader probes for main protease of SARS-CoV-2

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has afflicted many lives and led to approvals of drugs and vaccines for emergency use. Even though vaccines have emerged, the high mortality of COVID-19 and its insurgent proliferation throughout the masses commands an innovative therapeutic proposition for the treatment. Targeted protein degradation has been applied to various disease domains and we propose that it could be incredibly beneficial to tackle the current pandemic. In this study, we have attempted to furnish insights on the design of suitable PROTACs for the main protease (M^pro) of SARS-CoV-2, a protein that is considered to be an essential target for viral replication. We have employed protein-protein docking to predict the possible complementarity between a cereblon E3 ligase and M^pro of SARS-CoV-2, and estimate possible linker length. Molecular Dynamic simulation and analysis on generated ternary complexes demonstrated stable interactions that suggested that designed PROTAC has a potential to cause degradation. The superior characteristics rendered by PROTACS led us to propose them as possibly the next-generation antiviral drugs for SARS-CoV-2.

Graphical Abstract

Communicated by Ramaswamy H. Sarma

Keywords:

• PROTAC
• SARS-CoV-2
• main protease
• protein-protein docking
• MD simulation

Acknowledgments

The authors thank the Director, National Institute of Pharmaceutical Education and Research (NIPER), SAS. Nagar, Ministry of Chemicals and fertilizers, Gov. of India for providing facility to carry out this work. The authors also thank DST (Dept. of Science and Technology) and CSIR (Council of Scientific and Industrial Research), New Delhi for the computational infrastructure.

Disclosure statement

No potential conflict of interest was reported by the authors.

Author contributions

M. E. Sobhia (MES) designed the study. All the authors contributed to the computations, analysis, and preparation of the manuscript.