Identification of high affinity and low molecular alternatives of boceprevir against SARS-CoV-2 main protease: A virtual screening approach

Borkotoky, Subhomoi; Banerjee, Manidipa; Modi, Gyan; Dubey, Vikash Kumar

doi:10.1016/j.cplett.2021.138446

Cited by 17 publications

(12 citation statements)

References 42 publications

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“…Molecular Dynamics simulation and studies are routinely used along with molecular docking to gain advanced insights into mechanisms involving protein-ligand interactions, small molecules, peptides, or even nanoparticles 38 , 39 . We performed molecular dynamics and simulation of the three protein-ligand complexes using the GROMACS v.2018 39 , 42 . The complexes were chosen based on the specific high-affinity drugs that showed stable interactions with PDB ID:7DDN and alpha strain modelled spike proteins.…”

Section: Methodsmentioning

confidence: 99%

“…Isotropic NPT equilibration was also carried using the widely accepted Parinello-Rahman coupling having a time constant of 2 fs and reference pressure of 1bar. We employed the standard Berendsen thermostat Velocity recoupling method at 310K with no pressure coupling in the NVT step, time constant being 2 fs 39 , 41 , 42 . The final MD production step was run using leapfrog integration using Nose-Hoover and Parinello-Rahman Couplings [ 43 ] and a time step of 2 fs [ 42 ].…”

Section: Methodsmentioning

confidence: 99%

“…We employed the widely used Poisson Boltzmann Surface Area (PBSA) free energy analysis method to check the complexes’ post-simulation binding energy and affinity. This algorithm to compute protein-ligand energy complexes’ free energy is well accepted and highly used for such purposes 39 , 42 , 45 , 46 . We used the g_mmpbsa utility of the GROMACS to calculate the free energy of the complex and the per residue-free energy analysis.…”

Section: Methodsmentioning

confidence: 99%

“…We used the g_mmpbsa utility of the GROMACS to calculate the free energy of the complex and the per residue-free energy analysis. The g_mmpbsa tool computes the energy and non-polar solvation energy using the standard equation: Gbind= E elec + E VDW + G polar + G SASA 39 , 42 , 47 . …”

Section: Methodsmentioning

confidence: 99%

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Drugs repurposing against SARS-CoV2 and the new variant B.1.1.7 (alpha strain) targeting the spike protein: molecular docking and simulation studies

Pande¹,

Kundu²,

Srivastava³

2021

Heliyon

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Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2) is responsible for the global COVID-19 pandemic and millions of deaths worldwide. In December 2020, a new alpha strain of SARS-CoV2 was identified in the United Kingdom. It was referred to as VUI 202012/01 (Alpha strain modelled under investigation, 2020, month 12, number 01). The interaction between spike protein and ACE2 receptor is a prerequisite for entering virion into the host cell. The present study is focussed on the spike protein of the SARS-COV 2, involving the comparison of binding affinity of new alpha strain modelled spike with previous strain spike (PDB ID:7DDN) using in silico molecular docking, dynamics and simulation studies. The molecular docking studies of the alpha strain modelled spike protein confirmed its higher affinity for the ACE2 receptor than the spike protein of the dominant strain. Similar computational approaches have also been used to investigate the potency of FDA approved drugs from the ZINC Database against the spike protein of new alpha strain modelled and old ones. The drug molecules which showed strong affinity for both the spike proteins are then subjected to ADME analysis. The low overall binding energy of Conivaptan (-107.503 kJ/mol) and Trosec (-94.029 kJ/mol) is indicative of their strong binding affinities, well supported by interactions with critical residues.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Drugs repurposing against SARS-CoV2 and the new variant B.1.1.7 (alpha strain) targeting the spike protein: molecular docking and simulation studies

Pande¹,

Kundu²,

Srivastava³

2021

Heliyon

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“…The structure consists of a conserved non-canonical HIS41-CYS145 dyad located within the cleft between domains I and II (Dai et al 2020 ). Moreover, it has been reported that [LEU-GLN↓ (SER, ALA, GLY)] (↓: cleavage site) is the cleavage site in M pro (Borkotoky et al 2021 ). No human protease has been found to have such cleavage selectivity, and these functional characteristics make M pro an appealing target for drug development investigations (Ullrich and Nitsche 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Naturally occurring anthraquinones as potential inhibitors of SARS-CoV-2 main protease: an integrated computational study

et al. 2022

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The novel coronavirus disease (COVID-19) has spread throughout the globe, affecting millions of people. The World Health Organization (WHO) has declared this infectious disease a pandemic. At present, several clinical trials are going on to identify possible drugs for treating this infection. SARS-CoV-2 M pro is one of the most critical drug targets for the blockage of viral replication. The aim of this study was to identify potential natural anthraquinones that could bind to the active site of SARS-CoV-2 main protease and stop the viral replication. Blind molecular docking studies of 13 anthraquinones and one control drug (Boceprevir) with SARS-CoV-2 M pro were carried out using the SwissDOCK server, and alterporriol-Q that showed the highest binding affinity towards M pro were subjected to molecular dynamics simulation studies. This study indicated that several antiviral anthraquinones could prove to be effective inhibitors for SARS-CoV-2 M pro of COVID-19 as they bind near the active site having the catalytic dyad, HIS41 and CYS145 through non-covalent forces. The anthraquinones showed less inhibitory potential as compared to the FDA-approved drug, boceprevir. Among the anthraquinones studied , alterporriol-Q was found to be the most potent inhibitor of SARS-CoV-2 M pro . Further, MD simulation studies for M pro - alterporriol-Q system suggested that alterporriol-Q does not alter the structure of M pro to a significant extent. Considering the impact of COVID-19, identification of alternate compounds like alterporriol-Q that could inhibit the viral infection will help in accelerating the process of drug discovery. Supplementary Information The online version contains supplementary material available at 10.1007/s11756-021-01004-4.

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Novel chemical scaffold as potential drug against Leishmania donovani: Integrated computational and experimental approaches

Ranjan,

Dubey

2023

J of Cellular Biochemistry

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In this study, we have screened a large number of Food and Drug Administration‐approved compounds for novel anti‐leishmanial molecules targeting the citrate synthase enzyme of the parasite. Based on their docking and molecular dynamic simulation statistics, five compounds were selected. These compounds followed Lipinski's rule of five. Additionally, in vitro, antileishmanial and cytotoxicity studies were performed. The three compounds, Abemaciclib, Bazedoxifene, and Vorapaxar, had shown effective anti‐leishmanial activities with IC50 values of 0.92 ± 0.02, 0.65 ± 0.09, and 6.1 ± 0.91 against Leishmania donovani promastigote and with EC50 values of 1.52 ± 0.37, 2.11 ± 0.38, 10.4 ± 1.27 against intramacrophagic amastigote without significantly harming macrophage cells. Among them, from in silico and antileishmanial activities studies, Abemaciclib had been selected based on their less binding energy, good antileishmanial activities, and also a significant difference in their binding energy with human citrate synthase for cell death mechanistic studies using flow cytometry and a DNA fragmentation assay. The action of this compound resulted in an increased reactive oxygen species production, depolarization of mitochondrial membrane potential, DNA damage, and an increase in the sub‐G1 cell population. These properties are the hallmarks of apoptosis which were further confirmed by apoptotic assay. Based on the above result, this anticancer compound Abemaciclib could be employed as a potential treatment option for leishmaniasis after further confirmation.

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Identification of high affinity and low molecular alternatives of boceprevir against SARS-CoV-2 main protease: A virtual screening approach

Cited by 17 publications

References 42 publications

Drugs repurposing against SARS-CoV2 and the new variant B.1.1.7 (alpha strain) targeting the spike protein: molecular docking and simulation studies

Drugs repurposing against SARS-CoV2 and the new variant B.1.1.7 (alpha strain) targeting the spike protein: molecular docking and simulation studies

Naturally occurring anthraquinones as potential inhibitors of SARS-CoV-2 main protease: an integrated computational study

Novel chemical scaffold as potential drug against Leishmania donovani: Integrated computational and experimental approaches

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