Integrated docking and enhanced sampling-based selection of repurposing drugs for SARS-CoV-2 by targeting host dependent factors

Abstract

Since the onset of global pandemic, the most focused research currently in progress is the development of potential drug candidates and clinical trials of existing FDA approved drugs for other relevant diseases, in order to repurpose them for the COVID-19. At the same time, several high throughput screenings of drugs have been reported to inhibit the viral components during the early course of infection but with little proven efficacies. Here, we investigate the drug repurposing strategies to counteract the coronavirus infection which involves several potential targetable host proteins involved in viral replication and disease progression. We report the high throughput analysis of literature-derived repurposing drug candidates that can be used to target the genetic regulators known to interact with viral proteins based on experimental and interactome studies. In this work we have performed integrated molecular docking followed by molecular dynamics (MD) simulations and free energy calculations through an expedite in silico process where the number of screened candidates reduces sequentially at every step based on physicochemical interactions. We elucidate that in addition to the pre-clinical and FDA approved drugs that targets specific regulatory proteins, a range of chemical compounds (Nafamostat, Chloramphenicol, Ponatinib) binds to the other gene transcription and translation regulatory proteins with higher affinity and may harbour potential for therapeutic uses. There is a rapid growing interest in the development of combination therapy for COVID-19 to target multiple enzymes/pathways. Our in silico approach would be useful in generating leads for experimental screening for rapid drug repurposing against SARS-CoV-2 interacting host proteins.

Communicated by Ramaswamy H. Sarma

Keywords:

• COVID19
• molecular dynamics simulation
• host proteins
• protein-protein interaction
• gene regulation
• enhanced sampling

Acknowledgements

D.P. thanks IITK for postdoctoral fellowship. A.K. thanks IITK and Prescience for financial support. JKS would like to acknowledge SERB/DST, India for the partial support. Prescience acknowledges the CSR funding of GST IN. Authors thank IITK for the supercomputing facility.

Author contributions

The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.

Disclosure statement

The authors declare no competing financial interests.