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 vaccine candidates and clinical trials of existing FDA approved drugs for other relevant diseases, in order to repurpose them for the COVID-19. 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 insilico process where the number of screened candidates reduces sequentially at every step based on physicochemical information. 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 protein with higher affinity and may harbour potential for therapeutic uses.<br>

Mechanistic insights of key host proteins and potential repurposed inhibitors regulating SARS‐CoV‐2 pathway

“…Various interactome studies have highlighted detailed information on crucial host regulatory proteins for which repurposed drugs are shown to be effective. It is in line with our previous study, 26 where we have done an exhaustive screening of existing drugs and human targets using molecular docking, molecular dynamics simulations, and free energy calculations. From this study, 26 we were able to filter out potential drug‐target combinations that not only have better docking scores, good free energy, and residence time but they are in clinical phase trials.…”

“…Interestingly, we found that drugs with high binding free energies were already in the clinical trial phase for COVID‐19. Especially the drug Silmitasertib targeting CK2, which showed good binding free energies in our previous work, 26 is already in phase II clinical trials. Similarly, the drug Zotatifin targeting the eIF4E elongation factor is in clinical trial phase I.…”

“…Our recent study 26 followed an exhaustive screening of FDA‐approved drugs against multiple host targets by using high throughput computational screening 27 utilizing molecular docking, all‐atom molecular dynamics simulations including solvent and state‐of‐the‐art free energy calculations. The multi‐target multi‐ligand enhanced sampling approach provides highly selective off‐target drug combinations with stable affinities.…”

“…Once we have the free energy, we convert it to probability. Then we average over probabilities and later re‐calculate the averaged free energy from averaged probability ( F = −k T ln P ) ( F —free energy, k—Boltzmann constant, T —temperature, P —probability) 26,51 …”

The Mode of Therapeutic Action of 2-deoxy D-glucose: Anti- Viral or Glycolysis Blocker?

“…The interaction of 2-DG with all the four antiviral proteins was computationally investigated using PRinMTML-ESS platform (https://www.prescience.in/prins3) which uses the combination of molecular docking at the binding site of protein followed by all atom molecular dynamic simulation of the best-docked pose in water for determining the stability of the protein-ligand bound structure and finally enhanced free energy sampling for better understand the binding interaction of the ligand with the protein. The same methodology has been used for screening large number of new chemical candidates for 3CL pro in our earlier work 13 and the multi-target multi-ligand approach has been used in our high throughput analysis of literature derived repurposing drug candidates for SAR-CoV-2 that can be used to target the genetic regulators known to interact with viral proteins based on experimental and interactome studies 14 In our study, we have initially analysed the interaction of 2-DG with four viral proteins 3C-like protease (3CL pro ), non-structural protein 16 (Nsp16), papain-like cysteine protease (PL pro ) and RNA-dependent RNA polymerase (RdRp) which take part in replication and translation mechanism. Establishment of the viral replication and transcription complex (RTC) that includes, amongst others, RNA-processing and RNA-modifying enzymes and an RNA proofreading function essential for maintaining the integrity of the >30kb coronavirus genome 15 is crucial for virus replication and thus a promising target for antivirals against SARS-CoV-2.…”