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Pharmacophore Modelling-Based Drug Repurposing Approaches for SARS-CoV-2 Therapeutics.

ABSTRACT: The recent outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a devastating effect globally with no effective treatment. The swift strategy to find effective treatment against coronavirus disease 2019 (COVID-19) is to repurpose the approved drugs. In this pursuit, an exhaustive computational method has been used on the DrugBank compounds targeting nsp16/nsp10 complex (PDB code: 6W4H). A structure-based pharmacophore model was generated, and the selected model was escalated to screen DrugBank database, resulting in three compounds. These compounds were subjected to molecular docking studies at the protein-binding pocket employing the CDOCKER module available with the Discovery Studio v18. In order to discover potential candidate compounds, the co-crystallized compound S-adenosyl methionine (SAM) was used as the reference compound. Additionally, the compounds remdesivir and hydroxycholoroquine were employed for comparative docking. The results have shown that the three compounds have demonstrated a higher dock score than the reference compounds and were upgraded to molecular dynamics simulation (MDS) studies. The MDS results demonstrated that the three compounds, framycetin, kanamycin, and tobramycin, are promising candidate compounds. They have represented a stable binding mode at the targets binding pocket with an average protein backbone root mean square deviation below 0.3 nm. Additionally, they have prompted the hydrogen bonds during the entire simulations, inferring that the compounds have occupied the active site firmly. Taken together, our findings propose framycetin, kanamycin, and tobramycin as potent putative inhibitors for COVID-19 therapeutics.

SUBMITTER: Rampogu S

PROVIDER: S-EPMC8141588 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Drug repositioning (also referred to as drug repurposing) is the method of exploring novel therapeutic indications for Food and Drug Administration-approved clinically implemented drugs. The unique strategy of drug repositioning is used to boost the drug development process since drug discovery is an expensive, arduous, cumbersome, and high-risk procedure. Recently, several pharmaceutical firms have used the drug repositioning technique in their drug discovery and development programs to develop new medications based on the identification of new therapeutic targets. This technique is extremely effective, saves time, is comparatively economical, and has a low chance of failure. Developing appropriate treatment measures to inhibit the spread of Coronavirus disease-2019 (COVID-19) is currently a top priority. As a result, several studies were conducted to build novel therapeutic molecules using diverse strategies of drug repurposing to discover drug candidates against COVID-19 infection that can act as substantial inhibitors against virus particles. By implementing virtual screening of drug libraries, it is possible to identify potential drugs through drug repurposing. A molecular docking approach and calculation of binding free energy are used to estimate binding affinity and drug–receptor interactions. Drug-repurposing methodologies can be divided into three categories: target-oriented, drug-oriented, and disease-oriented, based on the gathered data about the various physicochemical, pharmacokinetic and pharmacological features of a drug candidate. Using computational methods such as homology modeling and molecular similarity, this methodology aids in determining the binding interaction of drug molecules with the target protein of the virus. In this book chapter, we explore a typical set of currently utilized computational techniques for identifying repurposable drug molecules for COVID-19, as well as their supporting databases. We also assess promising drugs anticipated by computational approaches to drugs currently being evaluated in clinical trials. Moreover, we also examine the takeaways from the evaluated research efforts, such as how to competently combine bioinformatics tools with experimental work and suggest a fully integrated drug-repurposing approach to combat the deadly COVID-19 infection.

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Pharmacophore Modelling-Based Drug Repurposing Approaches for SARS-CoV-2 Therapeutics.

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