Identification of potential cruzain inhibitors using <i>de novo</i> design, molecular docking and dynamics simulations studies

Bhowmick, Shovonlal; Chorge, Rekha Dhondiram; Jangam, Chaitanya Sadashiv; Bharatrao, Lomate Dhanraj; Patil, Pritee Chunarkar; Chikhale, Rupesh; Islam, Ataul

doi:10.1080/07391102.2019.1664334

Cited by 6 publications

(4 citation statements)

References 14 publications

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“…The binding free energy was then determined through the Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) method with the help of g_mmpbsa tool (Islam & Pillay, 2019, 2020. Theory and details of this method have been given in our previous publication (Bhowmick et al, 2019;Parida et al, 2020).…”

Section: Molecular Dynamics Simulationmentioning

confidence: 99%

Identification of bioactive compounds fromGlycyrrhiza glabraas possible inhibitor of SARS-CoV-2 spike glycoprotein and non-structural protein-15: a pharmacoinformatics study

Sinha

Prasad

Islam

et al. 2020

Journal of Biomolecular Structure and Dynamics

108

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Aim: In view of the strong immunomodulatory and antiviral activity of andrographolide and its derivative, the present study aimed to investigate the binding a nities of andrographolide and its derivative 14deoxy-11,12-didehydroandrographolide with 3 major targets of COVID-19 i.e. 3CLpro, PLpro and spike protein followed by their gene-set enrichment analysis with special reference to immune modulation. Materials and methods: SMILES of the compounds were retrieved from DigepPred database and the proteins identi ed were queried in STRING to evaluate the protein-protein interaction and modulated pathways were identi ed concerning the KEGG database. Drug-likeness and ADMET pro les were evaluated using MolSoft and admet SAR 2.0, respectively. Molecular docking was carried using autodock 4.0. Results: Andrographolide and 14-Deoxy-11,12-didehydroandrographolide were predicted to have a high binding a nity with papain-like protease i.e.-6.7 kcal/mol and-6.5 kcal/mol, respectively while they interact with equal binding energies with 3clpro (-6.8 kcal/mol) and spike protein (-6.9 kcal/mol). Network pharmacology analysis revealed that both compounds modulated the immune system through the regulation of chemokine signaling pathway, Rap1 signaling pathway, Cytokine-cytokine receptor interaction, MAPK signaling pathway, NF-kappa B signaling pathway, Rassignaling pathway, p53 signaling pathway, HIF-1 signaling pathway, and Natural killer cell-mediated cytotoxicity. Although the 14deoxy-11,12-didehydroandrographolide scored higher drug-likeness character, it showed less potency to interaction with targeted proteins of COVID-19. Conclusion: The study suggests the strong interaction of the andrographolide and its derivative 14-deoxy-11,12-didehydroandrographolide against target proteins associated with COVID-19. Further, network pharmacology analysis elucidated the different pathways of immunomodulation. However, clinical research should be conducted to con rm the current ndings.

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Section: Molecular Dynamics Simulationmentioning

confidence: 99%

Identification of bioactive compounds fromGlycyrrhiza glabraas possible inhibitor of SARS-CoV-2 spike glycoprotein and non-structural protein-15: a pharmacoinformatics study

Sinha

Prasad

Islam

et al. 2020

Journal of Biomolecular Structure and Dynamics

108

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“…Final production simulations were performed in the isothermal isobaric (NPT) ensemble at 300 K, using an external bath with a coupling constant of 0.1 ps, the total simulation time achieved was 100 ns. The pressure was kept constant (1 bar) by using pressure coupling with the time constant set to 1 ps [ 30 ]. The trajectories were stored at every 2 ps during the simulation and trajectories analyzed using built-in commands of AMBER18.…”

Section: Methodsmentioning

confidence: 99%

Effective Drug Candidates against Global Pandemic of Novel Corona Virus (nCoV-2019): A Probability Check through Computational Approach for Public Health Emergency

et al. 2023

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The infection of a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) started form Wuhan, Chinais a devastating and the incidence rate has increased worldwide. Due to the lack of effective treatment against SARS-CoV-2, various strategies are being tested in China and throughout the world, including drug repurposing. To identify the potent clinical antiretroviral drug candidate against pandemic nCov-19 through computational tools. In this study, we used molecular modelling tool (molecular modelling and molecular dynamics) to identify commercially available drugs that could act on protease proteins of SARS-CoV-2. The result showed that Saquinavir, an antiretroviral medication can be used as a first line agent to treat SARS-CoV-2 infection. Saquinavir showed promising binding to the protease active site compared to other possible antiviral agents such as Nelfinavir and Lopinavir. Structural flexibility is one of the important physical properties that affect protein conformation and function and taking this account we performed molecular dynamics studies. Molecular dynamics studies and free energy calculations suggest that Saquinavir binds better to the COVID-19 protease compared to other known antiretrovirals. Our studies clearly propose repurposing of known protease inhibitors for the treatment of COVID-19 infection. Previously ritonavir and lopinavir were proved an important analogues for SARS and MERS in supressing these viruses. In this study it was found that saquinavir has exhibited good G-score and E-model score compared to other analogues. So saquinavir would be prescribe to cure for nCov-2019 either single drug or maybe in combination with ritonavir.

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“…Trajectories of docked complexes used to calculate binding energies using Van der Waal, electrostatic, polar solvation, SASA, and Schrodinger binding and docking with protein carried out using Glide docking module. The molecular mechanics generalised Born surface area (MM-GBSA) method AMBER18 was used to measure the receptor and ligands' binding strength quantitatively [ 16 ]. The average interaction energies of all the ten compounds, BIC and ENZ, was calculated for 100 ns of MD trajectories [ 13 ].…”

Section: Methodsmentioning

confidence: 99%

Design, synthesis and evaluation of novel enzalutamide analogues as potential anticancer agents

Bhole

Chikhale

Wavhale

et al. 2021

Heliyon

Self Cite

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The androgen receptor inhibitor, Enzalutamide, proved effective against castration resistance prostate cancer, has demonstrated clinical benefits and increased survival rate in men. However, AR mutation (F876L) converts Enzalutamide from antagonist to agonist indicating a rapid evolution of resistance. Hence, our goal is to overcome this resistance mechanism by designing and developing novel Enzalutamide analogues. We designed a dataset of Enzalutamide derivatives using Enzalutamide's shape and electrostatic features to match with pharmacophoric features essential for tight binding with the androgen receptor. Based on this design strategy ten novel derivatives were selected including 5,5-dimethyl-3-(6-substituted benzo[d]thia/oxazol-2-yl)-2-thioxo-1-(4-(trifluoromethyl)pyridin-2-yl)imidazolidin-4-one ( 6a-j ) for synthesis. All the compounds were evaluated in-vitro on prostate cancer cell lines DU-145, LNCaP and PC3. Interestingly, two compounds 3-(6-hydroxybenzo[d]thiazol-2-yl)-5,5-dimethyl-2-thioxo-1-(4-(trifluoromethyl)pyridin-2-yl) imidazolidin-4-one ( 6c , IC 50 – 18.26 to 20.31μM) and 3-(6-hydroxybenzo[d]oxazol-2-yl)-5,5-dimethyl -2-thioxo- 1- (4-(trifluoromethyl) pyridin-2-yl)imidazolidin-4-one ( 6h , IC 50 – 18.26 to 20.31μM) were successful with promising in-vitro antiproliferative activity against prostate cancer cell lines. The binding mechanism of potential androgen receptor inhibitors was further studied by molecular docking, molecular dynamics simulations and MM-GBSA binding free energy calculations and found in agreement with the in vitro studies. It provided strong theoretical support to our hypothesis.

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Identification of potential cruzain inhibitors using de novo design, molecular docking and dynamics simulations studies

Cited by 6 publications

References 14 publications

Identification of bioactive compounds fromGlycyrrhiza glabraas possible inhibitor of SARS-CoV-2 spike glycoprotein and non-structural protein-15: a pharmacoinformatics study

Identification of bioactive compounds fromGlycyrrhiza glabraas possible inhibitor of SARS-CoV-2 spike glycoprotein and non-structural protein-15: a pharmacoinformatics study

Effective Drug Candidates against Global Pandemic of Novel Corona Virus (nCoV-2019): A Probability Check through Computational Approach for Public Health Emergency

Design, synthesis and evaluation of novel enzalutamide analogues as potential anticancer agents

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