E-pharmacophore modelling, virtual screening, molecular dynamics simulations and in-silico ADME analysis for identification of potential E6 inhibitors against cervical cancer

Kumar, Avinash; Rathi, Ekta; Kini, Suvarna G.

doi:10.1016/j.molstruc.2019.04.023

Cited by 62 publications

(31 citation statements)

References 25 publications

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“…There is no consensus about the duration of a molecular dynamics simulation, but it has been found that longer simulations do not necessarily improve binding free energy calculations (Hou et al, 2011). We chose 20 ns as a result of a literature search, in which simulation times ranged from 15 ns (one protein-ligand complex) to 200 ns (several protein-ligand complexes) (Kumar et al, 2019a;Mittal et al, 2020). To define the duration of a simulation run, the complexity of the phenomena under study and the size of the system should be considered, also depending directly on the available computer power.…”

Section: Discussionmentioning

confidence: 99%

Virtual screening of approved drugs as potential SARS-CoV-2 main protease inhibitors

Jiménez-Alberto

Ribas‐Aparicio

Aparicio-Ozores

et al. 2020

Computational Biology and Chemistry

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The global emergency caused by COVID-19 makes the discovery of drugs capable of inhibiting SARS-CoV-2 a priority, to reduce the mortality and morbidity of this disease. Repurposing approved drugs can provide therapeutic alternatives that promise rapid and ample coverage because they have a documented safety record, as well as infrastructure for large-scale production. The main protease of SARS-CoV-2 (Mpro) is an excellent therapeutic target because it is critical for viral replication; however, Mpro has a highly flexible active site that must be considered when performing computer-assisted drug discovery. In this work, potential inhibitors of the main protease (Mpro) of SARS-Cov-2 were identified through a docking-assisted virtual screening procedure. A total of 4384 drugs, all approved for human use, were screened against three conformers of Mpro. The ligands were further studied through molecular dynamics simulations and binding free energy analysis. A total of nine currently approved molecules are proposed as potential inhibitors of SARS-CoV-2. These molecules can be further tested to speed the development of therapeutics against COVID-19.

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Section: Discussionmentioning

confidence: 99%

Virtual screening of approved drugs as potential SARS-CoV-2 main protease inhibitors

Jiménez-Alberto

Ribas‐Aparicio

Aparicio-Ozores

et al. 2020

Computational Biology and Chemistry

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“…To generate low energy state protein, energy minimization was done using OPLS3e (Optimized potential for liquid stimulation) force field and the prepared protein was used for molecular modelling. To generate a grid around the ligand, the receptor grid generation workflow was used by keeping all functional residues in the grid [29] .…”

Section: Methodsmentioning

confidence: 99%

“…The lowest energy 3D structures with correlated chiralities were generated at pH 7.0 ± 2.0 under the OPLS3e force field. In this process, all the ligands were pre-processed, which includes generation of tautomers, ionization state at pH 7.0 ± 2.0 using Epik, addition of hydrogen bond, charged group neutralization, and ligand geometry were optimized [29] .…”

Section: Methodsmentioning

confidence: 99%

Repurposing of existing FDA approved drugs for Neprilysin inhibition: An in-silico study

Sankhe

Rathi

Manandhar

et al. 2021

Journal of Molecular Structure

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Highlights Drug repurposing of FDA approved drugs from ZINC 12 database was done using the crystal structure of extracellular domain of human NEP (PDB ID: 5JMY ) The interactions with catalytic triad of HIS583, HIS587 and GLU646 are important for NEP inhibition. Based on XP molecular docking, binding energy, IFD-SP and MD simulation top 4 NEP inhibitors were identified. ZINC000000601283 and ZINC000003831594 were found to be stable during MD simulation and may act as NEP inhibitors.

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“…Determining physicochemical and ADMET properties employing computational approaches is a fast, robust, and accurate method [16]. We have evaluated the physicochemical and ADMET properties of RC002 (callophysin A), GA004 (nigricanoside A), GA006 (nigricanoside A dimethyl ester) using the SwissADME tool ( Table 3).…”

Section: Investigation Of Physicochemical and Admet Propertiesmentioning

confidence: 99%

Screening marine algae metabolites as high-affinity inhibitors of SARS-CoV-2 main protease (3CLpro): an in silico analysis to identify novel drug candidates to combat COVID-19 pandemic

et al. 2020

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The recent dissemination of SARS-CoV-2 from Wuhan city to all over the world has created a pandemic. COVID-19 has cost many human lives and created an enormous economic burden. Although many drugs/vaccines are in different stages of clinical trials, still none is clinically available. We have screened a marine seaweed database (1110 compounds) against 3CLpro of SARS-CoV-2 using computational approaches. High throughput virtual screening was performed on compounds, and 86 of them with docking score < − 5.000 kcal mol−1 were subjected to standard-precision docking. Based on binding energies (< − 6.000 kcal mol−1), 9 compounds were further shortlisted and subjected to extra-precision docking. Free energy calculation by Prime-MM/GBSA suggested RC002, GA004, and GA006 as the most potent inhibitors of 3CLpro. An analysis of ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) properties of RC002, GA004, and GA006 indicated that only RC002 (callophysin A, from red alga Callophycus oppositifolius) passed Lipinski’s, Veber’s, PAINS and Brenk’s filters and displayed drug-like and lead-like properties. Analysis of 3CLpro-callophysin A complex revealed the involvement of salt bridge, hydrogen bonds, and hydrophobic interactions. callophysin A interacted with the catalytic residues (His41 and Cys145) of 3CLpro; hence it may act as a mechanism-based competitive inhibitor. Docking energy and docking affinity of callophysin A towards 3CLpro was − 8.776 kcal mol−1 and 2.73 × 106 M−1, respectively. Molecular dynamics simulation confirmed the stability of the 3CLpro-callophysin A complex. The findings of this study may serve as the basis for further validation by in vitro and in vivo studies.

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E-pharmacophore modelling, virtual screening, molecular dynamics simulations and in-silico ADME analysis for identification of potential E6 inhibitors against cervical cancer

Cited by 62 publications

References 25 publications

Virtual screening of approved drugs as potential SARS-CoV-2 main protease inhibitors

Virtual screening of approved drugs as potential SARS-CoV-2 main protease inhibitors

Repurposing of existing FDA approved drugs for Neprilysin inhibition: An in-silico study

Screening marine algae metabolites as high-affinity inhibitors of SARS-CoV-2 main protease (3CLpro): an in silico analysis to identify novel drug candidates to combat COVID-19 pandemic

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