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In silico studies of Potency and safety assessment of selected trial drugs for the treatment of COVID-19.

ABSTRACT: SARS-CoV-2 has caused millions of infections and hundreds of thousands of deaths globally. Presently, no cure for SARS-CoV-2 infection is available; thus, all hands are on deck for new drug discovery. Although, several studies have reported the potentials of some already approved drugs for the treatment of COVID-19. This study attempted to compare the potency and safety of some these trial drugs via in silico methods. The binding affinity and interactions of the trial drugs with proteins involved in viral polyprotein processing (Papain like protease (PLpro) and Chymotrypsin like-protease (3-CLpro), viral replication (RNA dependent RNA polymerase (RdRp)) and host protease were studied in this work. The pharmacokinetic properties and toxicity potentials of the trial drugs were also predicted using vNN Web Server for ADMET Predictions. From the results, Merimepodib and Dexamethaxone demonstrated the most significant inhibitory potential against the PLpro. The binding affinity (∆G°) for merimepodib was - 7.2 kcal/mol while the inhibition constant was 6.3 µM. The binding affinity of the inhibitors for CLpro ranged from - 5.6 to - 9.5 kcal/mol. whereas Lopinavir (- 7.7 kcal/mol) exhibited the strongest affinity for RdRp. Overall, our results showed that all the ligands have a higher affinity for the 3-Chymotrypsin like protease than the other proteins (PLpro, RdRp, and Host protease). Among these compounds lopinavir, merimepodib and dexamethasone could be inhibitors with potentials for the treatment of SARS-CoV-2. However, the only dexamethasone has attractive pharmacokinetic and toxicity properties probable for drug development; therefore, our study provides a basis for developing effective drugs targeting a specific protein in the SARS-CoV-2 life cycle.

Supplementary information

The online version contains supplementary material available at 10.1007/s40203-021-00105-x.

SUBMITTER: Adegbola PI

PROVIDER: S-EPMC8295030 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:INTRODUCTION:Several antiretroviral drugs are being considered for the treatment of COVID-19, the disease caused by a newly identified coronavirus, (SARS-CoV-2). We systematically reviewed the clinical outcomes of using antiretroviral drugs for the prevention and treatment of coronaviruses and planned clinical trials. METHODS:Three databases were screened from inception to 30 March 2020 for studies reporting clinical outcomes of patients with SARS, MERS or COVID-19 treated with antiretrovirals. RESULTS:From an initial screen of 433 titles, two randomized trials and 24 observational studies provided clinical outcome data on the use of antiretroviral drugs; most studies reported outcomes using LPV/r as treatment. Of the 21 observational studies reporting treatment outcomes, there were three studies among patients with SARS, six studies among patients with MERS and 12 studies among patients with COVID-19. In one randomized trial 99 patients with severe COVID-19 illness were randomized to receive LPV/r (400/100 mg twice a day) and 100 patients to standard of care for 14 days: LPV/r was not associated with a statistically significant difference in time to clinical improvement, although LPV/r given within 12 days of symptoms was associated with shorter time to clinical improvement; 28 day mortality was numerically lower in the LPV/r group (14/99) compared to the control group (25/100), but this difference was not statistically significant. The second trial found no benefit. The certainty of the evidence for the randomized trials was low. In the observational studies 3 out of 361 patients who received LPV/r died; the certainty of evidence was very low. Three studies reported a possible protective effect of LPV/r as post-exposure prophylaxis. Again, the certainty of the evidence was very low due to uncertainty due to limited sample size. CONCLUSIONS:On the basis of the available evidence it is uncertain whether LPV/r and other antiretrovirals improve clinical outcomes or prevent infection among patients at high risk of acquiring COVID-19.

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In silico studies of Potency and safety assessment of selected trial drugs for the treatment of COVID-19.

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