Drug repurposing against main protease and RNA-dependent RNA polymerase of SARS-CoV-2 using molecular docking, MM-GBSA calculations and molecular dynamics.

A virus called severe acute respiratory distress syndrome coronavirus type 2 (SARS-CoV-2) is the causing organism of coronavirus disease 2019 (COVID-19), which has severely affected human life and threatened public health. The pandemic took millions of lives worldwide and caused serious negative effects on human society and the economy. SARS-CoV-2 main protease (Mpro) and RNA-dependent RNA polymerase (RdRp) are interesting targets due to their crucial role in viral replication and growth. Since there is only one approved therapy for COVID-19, drug repurposing is a promising approach to finding molecules with potential activity against COVID-19 in a short time and at minimal cost. In this study, virtual screening was performed on the ChEMBL library containing 9923 FDA-approved drugs, using various docking filters with different accuracy. The best drugs with the highest docking scores were further examined for molecular dynamics (MD) studies and MM-GBSA calculations. The results of this study suggest that nadide, cangrelor and denufosol are promising potential candidates against COVID-19. Further in vitro, preclinical and clinical studies of these candidates would help to discover safe and effective anti-COVID-19 drugs.

Drug repurposing for SARS-CoV-2 main protease: Molecular docking and molecular dynamics investigations

The current novel corona virus illness (COVID-19) is a developing viral disease that was discovered in 2019. There is currently no viable therapeutic strategy for this illness management. Because traditional medication development and discovery has lagged behind the threat of emerging and re-emerging illnesses like Ebola, MERS-CoV, and, more recently, SARS-CoV-2. Drug developers began to consider drug repurposing (or repositioning) as a viable option to the more traditional drug development method. The goal of drug repurposing is to uncover new uses for an approved or investigational medicine that aren't related to its original use. The main benefits of this strategy are that there is less developmental risk and that it takes less time because the safety and pharmacologic requirements are met. The main protease (Mpro) of corona viruses is one of the well-studied and appealing therapeutic targets. As a result, the current research examines the molecular docking of Mpro (PDB ID: 5R81) conjugated repurposed drugs. 12,432 approved drugs were collected from ChEMBL and drugbank libraries, and docked separately into the receptor grid created on 5R81, using the three phases of molecular docking including high throughput virtual screening (HTVS), standard precision (SP), and extra precision (XP). Based on docking scores and MM-GBSA binding free energy calculation, top three drugs (kanamycin, sulfinalol and carvedilol) were chosen for further analyses for molecular dynamic simulations. Graphical Image 1

Identification of novel transmembrane Protease Serine Type 2 drug candidates for COVID-19 using computational studies.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) emergence has resulted in a global health crisis. As a consequence, discovering an effective therapy that saves lives and slows the spread of the pandemic is a global concern currently. In silico drug repurposing is highly regarded as a precise computational method for obtaining fast and reliable results. Transmembrane serine-type 2 (TMPRSS2) is a SARS CoV-2 enzyme that is essential for viral fusion with the host cell. Inhibition of TMPRSS2 may block or lessen the severity of SARS-CoV-2 infection. In this study, we aimed to perform an in silico drug repurposing to identify drugs that can effectively inhibit SARS-CoV-2 TMPRSS2. As there is no 3D structure of TMPRSS2 available, homology modeling was performed to build the 3D structure of human TMPRSS2. 3848 world-approved drugs were screened against the target. Based on docking scores and visual outcomes, the best-fit drugs were chosen. Molecular dynamics (MD) and density functional theory (DFT) studies were also conducted. Five potential drugs (Amikacin, isepamicin, butikacin, lividomycin, paromomycin) exhibited promising binding affinities. In conclusion, these findings empower purposing these agents.