Pharmacophore model and atom-based 3D quantitative structure activity relationship (QSAR) of human immunodeficiency virus-1 (HIV-1) capsid assembly inhibitors

Bhole, Ritesh P.; Bonde, Chandrakant; Bonde, S C; Chikhale, Rupesh; Wavhale, Ravindra D.

doi:10.1080/07391102.2020.1715258

Cited by 24 publications

(8 citation statements)

References 19 publications

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“…All ten ligands, ENZ and BIC, docked complexes simulated using AMBER18 package [ 12 , 13 ] Topology and coordinate parameters for androgen receptor generated with an AMBER99SB force field. The ligands were parametrised with a general amber force field (GAFF)in the xLeap module.…”

Section: Methodsmentioning

confidence: 99%

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

Bhole

Chikhale

Wavhale

et al. 2021

Heliyon

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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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Section: Methodsmentioning

confidence: 99%

“…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

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“…Quantitative structure-activity relationships (QSAR), biological tests, and pharmacophore analysis can all be used to improve and create new leads [26][27][28]. Structurebased drug design assists in creating more potent and signifcant molecules during the drug development process [29][30][31].…”

Section: Introductionmentioning

confidence: 99%

Molecular Dynamics Simulation and Pharmacoinformatic Integrated Analysis of Bioactive Phytochemicals from Azadirachta indica (Neem) to Treat Diabetes Mellitus

Abdullah¹,

Biswas²,

Sahabuddin³

et al. 2023

Journal of Chemistry

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Diabetes mellitus is a chronic hormonal and metabolic disorder in which our body cannot generate necessary insulin or does not act in response to it, accordingly, ensuing in discordantly high blood sugar (glucose) levels. Diabetes mellitus can lead to systemic dysfunction in the multiorgan system, including cardiac dysfunction, severe kidney disease, lowered quality of life, and increased mortality risk from diabetic complications. To uncover possible therapeutic targets to treat diabetes mellitus, the in silico drug design technique is widely used, which connects the ligand molecules with target proteins to construct a protein-ligand network. To identify new therapeutic targets for type 2 diabetes mellitus, Azadirachta indica is subjected to phytochemical screening using in silico molecular docking, pharmacokinetic behavior analysis, and simulation-based molecular dynamic analysis. This study has analyzed around 63 phytochemical compounds, and the initial selection of the compounds was made by analyzing their pharmacokinetic properties by comparing them with Lipinski’s rule of 5. The selected compounds were subjected to molecular docking. The top four ligand compounds were reported along with the control drug nateglinide based on their highest negative molecular binding affinity. The protein-ligand interaction of selected compounds has been analyzed to understand better how compounds interact with the targeted protein structure. The results of the in silico analysis revealed that 7-Deacetyl-7-oxogedunin had the highest negative docking score of −8.9 Kcal/mol and also demonstrated standard stability in a 100 ns molecular dynamic simulation performed with insulin receptor ectodomain. It has been found that these substances may rank among the essential supplementary antidiabetic drugs for treating type 2 diabetes mellitus. It is suggested that more in vivo and in vitro research studies be carried out to support the conclusions drawn from this in silico research strategy.

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“…Various reports on use of FDA approved drugs like the antiviral agents specially the HIV protease inhibitors in the treatment of COVID-19 motivated us to perform computational studies. Our previous experience with HIV inhibitors has provided us with an insight in functioning of these antiviral agents [ 24 ]. Recent report of COVID-19 protease co-crystallised with a bound peptide (PDB-6LU7) has opened the gates for computational studies on this target.…”

Section: Introductionmentioning

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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Pharmacophore model and atom-based 3D quantitative structure activity relationship (QSAR) of human immunodeficiency virus-1 (HIV-1) capsid assembly inhibitors

Cited by 24 publications

References 19 publications

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

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

Molecular Dynamics Simulation and Pharmacoinformatic Integrated Analysis of Bioactive Phytochemicals from Azadirachta indica (Neem) to Treat Diabetes Mellitus

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

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