article · Journal of Biomolecular Structure and Dynamics
Computational screening evaluated 1,697 approved pharmaceuticals to assess their ability to inhibit the SARS-CoV-2 papain-like protease, an essential viral enzyme. Several existing treatments showed binding capabilities superior to a previously identified reference inhibitor. These included select antivirals such as ritonavir, cell protectives and antioxidants, antimicrobials, anthelmintics, blood pressure therapies, and antacids. Detailed molecular dynamics simulations and binding energy calculations were conducted on the ten most promising candidates with favourable pharmacokinetic profiles. From these simulations, phenformin, quercetin, and ritonavir demonstrated strong prospective binding affinities to the protease over fifty-nanosecond evaluations. Among them, phenformin exhibited the highest structural stability and energy metrics. By identifying established medications with strong predicted activity against the viral protease, this screening offers specific target options for further antiviral evaluation and rapid clinical repurposing efforts.
Developing new therapeutic drugs from scratch takes years of preclinical and clinical testing. Drug repurposing bypasses early toxicity and pharmacokinetic assessments by testing medications already confirmed safe in humans. Identifying existing treatments that bind to critical viral enzymes provides immediate candidate options to guide further antiviral research and accelerate the discovery of viable treatments during disease outbreaks.
This work represents very early-stage computational drug discovery. The findings provide pharmaceutical developers and clinical researchers with pre-screened drug candidates, particularly phenformin, quercetin, and ritonavir, for repurposing against SARS-CoV-2. Moving these computational predictions towards practical healthcare use would require subsequent laboratory validation, preclinical testing, and targeted clinical trials to verify antiviral efficacy and safe dosing in patients.
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SARS-CoV-2 or Coronavirus disease 19 (COVID-19) is a rapidly spreading, highly contagious, and sometimes fatal disease for which drug discovery and vaccine development are critical. SARS-CoV-2 papain-like protease (PL<sup>pro</sup>) was used to virtually screen 1697 clinical FDA-approved drugs. Among the top results expected to bind with SARS-CoV-2 PL<sup>pro</sup> strongly were three cell protectives and antioxidants (NAD+, quercitrin, and oxiglutatione), three antivirals (ritonavir, moroxydine, and zanamivir), two antimicrobials (doripenem and sulfaguanidine), two anticancer drugs, three benzimidazole anthelmintics, one antacid (famotidine), three anti-hypertensive ACE receptor blockers (candesartan, losartan, and valsartan) and other miscellaneous systemically or topically acting drugs. The binding patterns of these drugs were superior to the previously identified SARS CoV PL<sup>pro</sup> inhibitor, 6-mercaptopurine (6-MP), suggesting a potential for repurposing these drugs to treat COVID-19. The objective of drug repurposing is the rapid relocation of safe and approved drugs by bypassing the lengthy pharmacokinetic, toxicity, and preclinical phases. The ten drugs with the highest estimated docking scores with favorable pharmacokinetics were subjected to molecular dynamics (MD) simulations followed by molecular mechanics/generalized Born surface area (MM/GBSA) binding energy calculations. Phenformin, quercetin, and ritonavir all demonstrated prospective binding affinities for COVID-19 PL<sup>pro</sup> over 50 ns MD simulations, with binding energy values of -56.6, -40.9, and -37.6 kcal/mol, respectively. Energetic and structural analyses showed phenformin was more stable than quercetin and ritonavir. The list of the drugs provided herein constitutes a primer for clinical application in COVID-19 patients and guidance for further antiviral studies.Communicated by Ramaswamy H. Sarma.
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DOI: 10.1080/07391102.2020.1784291
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