Comparative assessment of RNA-dependent RNA polymerase (RdRp) inhibitors under clinical trials to control SARS-CoV2 using rigorous computational workflow

Goswami, Dweipayan

doi:10.1039/d1ra04460e

Cited by 16 publications

(10 citation statements)

References 68 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Furthermore, these in silico methodologies have additionally been used for strength appraisal of hydroxychloroquine against different expected target proteins of SARS-CoV-2 [ 52 ]. In these computational examinations, the reasoning is extremely fundamental that in the event that any of these metabolites serving as potential drug leads can intrude with the viral proteins, they can thwart the typical life pattern of the viral particle [ 53 – 55 ].…”

Section: Discussionmentioning

confidence: 99%

Perceiving SARS-CoV-2 Mpro and PLpro dual inhibitors from pool of recognized antiviral compounds of endophytic microbes: an in silico simulation study

et al. 2022

Self Cite

View full text Add to dashboard Cite

Coronavirus disease 2019 (COVID-19) persists and shook the global population where the endgame to this pandemic is brought on by developing vaccines in record-breaking time. Nevertheless, these vaccines are far from perfect where their efficiency ranges from 65 to 90%; therefore, vaccines are not the one only solution to overcome this situation, and apart from administration of vaccines, the scientific community is at quest for finding alternative solutions to incumber SARS-CoV-2 infection. In this study, our research group is keen on identifying a bioactive molecule that is independent in its mode of action from existing vaccines which can potentially target the SARS-CoV-2 virus replicative efficacy. Papain-like protease (PLpro) and main protease (Mpro) are the most lucrative targets of COVIDs against which the drugs can be developed, as these proteases play a vital role in the replication and development of viral particles. Researchers have modelled a compound such as GRL0617 and X77 as an inhibitor of Mpro and PLpro, respectively, but use of these compounds has several limitations on hosts like toxicity and solubility. Under the current study by deploying rigorous computational assessments, pool of microbial secondary metabolites was screened and handpicked to search a structural or functional analogue of GRL0617 and X77, with an idea to identify a compound that can serve as dual inhibitor for both PLpro and Mpro. From the manually curated database of known antiviral compounds from fungal origin, we found cytonic acids A and B to potentially serve as dual inhibitor of PLpro and Mpro.

show abstract

Section: Discussionmentioning

confidence: 99%

Perceiving SARS-CoV-2 Mpro and PLpro dual inhibitors from pool of recognized antiviral compounds of endophytic microbes: an in silico simulation study

et al. 2022

Self Cite

View full text Add to dashboard Cite

show abstract

“…arrhizus . Molecular docking was one of them which simply predicts the type of interaction that may occur between a protein and a ligand for a certain pose, but it does not predict the strength of the interaction [ 40 ], and hence MD simulation was also performed to validate the interaction of eugenol with fungal CYP51B. MD simulations aid in overcoming this limitation of molecular docking.…”

Section: Discussionmentioning

confidence: 99%

A Comprehensive in vitro and in silico Assessment on Inhibition of CYP51B and Ergosterol Biosynthesis by Eugenol in Rhizopus oryzae

et al. 2022

Self Cite

View full text Add to dashboard Cite

Mucormycosis, also known as Zygomycosis, is a disease caused by invasive fungi, predominantly Rhizopus species belonging to the Order of Mucorales . Seeing from the chemistry perspective, heterocyclic compounds with an "azole" moiety are widely employed as antifungal agent for minimising the effect of mucormycosis as a prescribed treatment. These azoles serve as non-competitive inhibitors of fungal CYP51B by predominantly binding to its heme moiety, rendering its inhibition. However, long-term usage and abuse of azoles as antifungal medicines has resulted in drug resistance among certain fungal pathogens. Hence, there is an unmet need to find alternative therapeutic compounds. In present study, we used various in vitro tests to investigate the antifungal activity of eugenol against R. oryzae/R. arrhizus , including ergosterol quantification to test inhibition of ergosterol production mediated antifungal action. The minimum inhibitory concentration (MIC) value obtained for eugenol was 512 μg/ml with reduced ergosterol concentration of 77.11 ± 3.25% at MIC/2 concentration. Further, the molecular interactions of eugenol with fungal CYP51B were meticulously studied making use of proteomics in silico study including molecular docking and molecular dynamics simulations that showed eugenol to be strongly interacting with heme in an identical fashion to that shown by azole drugs (in this case, clotrimazole was evaluated). This is the first of a kind study showing the simulation study of eugenol with CYP51B of fungi. This inhibition results in ergosterol synthesis and is also studied and compared with keeping clotrimazole as a reference. Graphical Abstract

show abstract

“…Pharmacophore mapping is a method for identifying the similar ligands to the reference drug from the database [ 66 ]. To consolidate the findings of docking the top hit, curcumin was chosen for further assessment, where MD simulations further provided the robust assessment of interaction of curcumin with BChE, as MD simulations provide best possible near to perfect predictions of ligand protein interactions [ 47 ]. To the best of our knowledge this is an holistic report for curcumin to inhibit the dipteran BChE and the claim is further validated by performing in vitro enzyme assay using Ellman’s protocol [ 14 , 62 , 67 ].…”

Section: Discussionmentioning

confidence: 99%

Extending the lore of curcumin as dipteran Butyrylcholine esterase (BChE) inhibitor: A holistic molecular interplay assessment

2022

Self Cite

View full text Add to dashboard Cite

Since its origin, the emergence of vector-borne infections has taken a toll on incalculable human lives. The use of chemical insecticides is one of the early known methods of vector control and although their use is still a prevalent way to combat insect population sadly the perils of insects related transmission still persists. Most commonly, the existing insecticides face the wrath of getting resisted repeatedly, paying way to develop resilient, efficient, and cost-effective natural insecticides. In this study, computational screening was performed using homology modelling, E-pharmacophore feature mapping, molecular docking, Density Function Theory (DFT) assessment, Molecular mechanics generalized Born surface area (MM-GBSA) based binding free energy calculations and Molecular Dynamics (MD) simulation to identify a potential lead phytochemical out of a manually curated library from published literature. The protein target used under this study is insect Butyrylcholine esterase (BChE). Additionally, in vitro insect (Aedes aegypti) BChE inhibition assay was also performed with the top phytochemical identified from in silico assessments. Our research highlights that curcumin leads to inhibition of enzyme BChE of Ae. aegypti. The identified mode of action of curcumin as an insect BChE inhibitor indicates the possibility of its use as an environment friendly and natural futuristic insecticide.

show abstract

Comparative assessment of RNA-dependent RNA polymerase (RdRp) inhibitors under clinical trials to control SARS-CoV2 using rigorous computational workflow

Abstract: Identifying the inhibitors for RNA-dependant-RNA polymerase (RdRp) of SARS-CoV2.

Cited by 16 publications

References 68 publications

Perceiving SARS-CoV-2 Mpro and PLpro dual inhibitors from pool of recognized antiviral compounds of endophytic microbes: an in silico simulation study

Perceiving SARS-CoV-2 Mpro and PLpro dual inhibitors from pool of recognized antiviral compounds of endophytic microbes: an in silico simulation study

A Comprehensive in vitro and in silico Assessment on Inhibition of CYP51B and Ergosterol Biosynthesis by Eugenol in Rhizopus oryzae

Extending the lore of curcumin as dipteran Butyrylcholine esterase (BChE) inhibitor: A holistic molecular interplay assessment

Contact Info

Product

Resources

About