Computer-aided discovery of bis-indole derivatives as multi-target drugs against cancer and bacterial infections: DFT, docking, virtual screening, and molecular dynamics studies

Gupta, Parth Sarthi Sen; Bhat, Haamid Rasool; Biswal, Satyaranjan; Rana, Malay Kumar

doi:10.1016/j.molliq.2020.114375

Cited by 37 publications

(19 citation statements)

References 96 publications

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“…The optimized ligands, as well as the co-ligand, α-ketoamide 13 b, were docked in the active site of SARS-CoV-2 Mpro after assigning the Gasteiger charges with AutoDock Vina [ 24 ], which uses the Lamarckian genetic algorithm (GA) in combination with grid-based energy estimation incorporated in PyRx [ 25 ]. The docking protocol adopted herein is the same as that used in other peer-reviewed works [ 26 , 27 ]. Due to the significant accuracy of AutoDock Vina, demonstrated in a recent benchmark study [ 28 ], we also used it for molecular docking.…”

Section: Methodsmentioning

confidence: 99%

Repurposing of FDA-approved drugs as potential inhibitors of the SARS-CoV-2 main protease: Molecular insights into improved therapeutic discovery

Ray¹,

Gupta²,

Panda³

et al. 2022

Computers in Biology and Medicine

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With numerous infections and fatalities, COVID-19 has wreaked havoc around the globe. The main protease (Mpro), which cleaves the polyprotein to form non-structural proteins, thereby helping in the replication of SARS-CoV-2, appears as an attractive target for antiviral therapeutics. As FDA-approved drugs have shown effectiveness in targeting Mpro in previous SARS-CoV(s), molecular docking and virtual screening of existing antiviral, antimalarial, and protease inhibitor drugs were carried out against SARS-CoV-2 Mpro. Among 53 shortlisted drugs with binding energies lower than that of the crystal-bound inhibitor α-ketoamide 13 b (−6.7 kcal/mol), velpatasvir, glecaprevir, grazoprevir, baloxavir marboxil, danoprevir, nelfinavir, and indinavir (−9.1 to −7.5 kcal/mol) were the most significant on the list (hereafter referred to as the 53-list). Molecular dynamics (MD) simulations confirmed the stability of their Mpro complexes, with the MMPBSA binding free energy (ΔG bind ) ranging between −124 kJ/mol (glecaprevir) and −28.2 kJ/mol (velpatasvir). Despite having the lowest initial binding energy, velpatasvir exhibited the highest ΔG bind value for escaping the catalytic site during the MD simulations, indicating its reduced efficacy, as observed experimentally. Available inhibition assay data adequately substantiated the computational forecast. Glecaprevir and nelfinavir (ΔG bind = −95.4 kJ/mol) appear to be the most effective antiviral drugs against Mpro. Furthermore, the remaining FDA drugs on the 53-list can be worth considering, since some have already demonstrated antiviral activity against SARS-CoV-2. Hence, theoretical pK i (K i = inhibitor constant) values for all 53 drugs were provided. Notably, ΔG bind directly correlates with the average distance of the drugs from the His41–Cys145 catalytic dyad of Mpro, providing a roadmap for rapid screening and improving the inhibitor design against SARS-CoV-2 Mpro.

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Section: Methodsmentioning

confidence: 99%

Repurposing of FDA-approved drugs as potential inhibitors of the SARS-CoV-2 main protease: Molecular insights into improved therapeutic discovery

Ray¹,

Gupta²,

Panda³

et al. 2022

Computers in Biology and Medicine

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“…As a result indole's design and selective function have been the focus of recent research [21]. A theoretical investigation of indole derivatitve as multitarget drugs against cancer and bacterial infections was published by Gupta et al [22]. In the present work, interaction of indole with DC under different solvents is reported.…”

Section: Introductionmentioning

confidence: 69%

Theoretical Investigation of the Modeling of Indole –dichlormethane Hydrogen Bonding in Different Solvents

Al‐Otaibi

Mary²,

Mary³

2021

Preprint

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Theoretical vibrational spectra of indole (IND) and its binary combination with dichloromethane (DC) in various solvents were computed to track the impact of molecular interactions on drug spectral characteristics. When transitioning from plain drug to complexes, 3561.26 cm− 1 mode of the IND displays a substantial shift in peak location. The 3561.26 band shows (~ 15.58) red shift upon dilution. The geometry of drug and IND-DC complex in various solvents was calculated using quantum chemical calculation utilizing DFT.

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“…The importance of MD simulation in vaccine design is undeniable as it provides information that can direct experimental validation. It has great significance to analyze the internal motions, conformational changes, stability, etc., of the complexes [40] , [41] . Using the MD trajectories, RMSD, RMSF, R g , hydrogen bond, SASA and binding free-energy of the complexes were computed to investigate their structural stabilities and binding strengths.…”

Section: Resultsmentioning

confidence: 99%

“…The binding free energies of the complex were calculated based on 5000 snapshots taken at an equal interval of time from 50 ns MD simulations. More information about the methods used in this study can be found in our previous works [40] , [41] .…”

Section: Methodsmentioning

confidence: 99%

Designing AbhiSCoVac - A single potential vaccine for all ‘corona culprits’: Immunoinformatics and immune simulation approaches

Choudhury

Gupta

Panda

et al. 2022

Journal of Molecular Liquids

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Computer-aided discovery of bis-indole derivatives as multi-target drugs against cancer and bacterial infections: DFT, docking, virtual screening, and molecular dynamics studies

Cited by 37 publications

References 96 publications

Repurposing of FDA-approved drugs as potential inhibitors of the SARS-CoV-2 main protease: Molecular insights into improved therapeutic discovery

Repurposing of FDA-approved drugs as potential inhibitors of the SARS-CoV-2 main protease: Molecular insights into improved therapeutic discovery

Theoretical Investigation of the Modeling of Indole –dichlormethane Hydrogen Bonding in Different Solvents

Designing AbhiSCoVac - A single potential vaccine for all ‘corona culprits’: Immunoinformatics and immune simulation approaches

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