Pharmacoinformatics study of Piperolactam A from Piper betle root as new lead for non steroidal anti fertility drug development

Amin, Sk. Abdul; Bhattacharya, P. K.; Basak, Souvik; Gayen, Shovanlal; Nandy, Ashis; Saha, Achintya

doi:10.1016/j.compbiolchem.2017.01.004

Cited by 27 publications

(11 citation statements)

References 27 publications

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“…Molecular docking studies obtained a total of 10 candidate molecules to inhibit Cdk5/p25. Since, molecular docking does not provide simulated physiological environment and real-time behavior of the drug-receptor interaction; therefore, molecular dynamics (MD) simulation was employed to identify the true positive inhibitors of Cdk5/p25 [ 35 , 36 , 58 ]. The root mean square deviation (rmsd) analysis is a key factor to evaluate the stability and successful execution of MD simulation [ 34 , 35 , 58 ].…”

Section: Discussionmentioning

confidence: 99%

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Computational Simulations Identified Two Candidate Inhibitors of Cdk5/p25 to Abrogate Tau-associated Neurological Disorders

Zeb

Son

Yoon

et al. 2019

Computational and Structural Biotechnology Journal

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Deregulation of Cdk5 is a hallmark in neurodegenerative diseases and its complex with p25 forms Cdk5/p25, thereby causes severe neuropathological insults. Cdk5/p25 abnormally phosphorylates tau protein, and induces tau-associated neurofibrillary tangles in neurological disorders. Therefore, the pharmacological inhibition of Cdk5/p25 alleviates tau-associated neurological disorders. Herein, computational simulations probed two candidate inhibitors of Cdk5/p25. Structure-based pharmacophore investigated the essential complementary chemical features of ATP-binding site of Cdk5 in complex with roscovitine. Resultant pharmacophore harbored polar interactions with Cys83 and Asp86 residues and non-polar interactions with Ile10, Phe80, and Lys133 residues of Cdk5. The chemical space of selected pharmacophore was comprised of two hydrogen bond donors, one hydrogen bond acceptor, and three hydrophobic features. Decoy test validation of pharmacophore obtained highest Guner-Henry score (0.88) and enrichment factor score (7.23). The screening of natural product drug-like databases by validated pharmacophore retrieved 1126 compounds as candidate inhibitors of Cdk5/p25. The docking of candidate inhibitors filtered 10 molecules with docking score >80.00 and established polar and non-polar interactions with the ATP-binding site residues of Cdk5/p25. Finally, molecular dynamics simulation and binding free energy analyses identified two candidate inhibitors of Cdk5/p25. During 30 ns simulation, the candidate inhibitors established <3.0 Å root mean square deviation and stable hydrogen bond interactions with the ATP-binding site residues of Cdk5/p25. The final candidate inhibitors obtained lowest binding free energies of −122.18 kJ/mol and − 117.26 kJ/mol with Cdk5/p25. Overall, we recommend two natural product candidate inhibitors to target the pharmacological inhibition of Cdk5/p25 in tau-associated neurological disorders.

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Section: Discussionmentioning

confidence: 99%

“…For docking analysis, the previously well-established procedure was followed [ [35] , [36] , [37] ]. In brief, the crystal structure of Cdk5/p25 (PDB ID: 1UNL ) was taken from Protein Data Bank ( https://www.rcsb.org/ ) [ 26 ].…”

Section: Methodsmentioning

confidence: 99%

Computational Simulations Identified Two Candidate Inhibitors of Cdk5/p25 to Abrogate Tau-associated Neurological Disorders

Zeb

Son

Yoon

et al. 2019

Computational and Structural Biotechnology Journal

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“…Many of these isolated aporphine alkaloids were isolated previously from Piper genus. Compound (1) and (2) have been isolated from P. officinarum (Salleh et al, 2014c) and P. betle (Lin et al, 2013), whilst the compound (3), (4), and (5) have been isolated from P. betle (Amin et al, 2017), P. taiwanense (Chen et al, 2004), and P. nigrum (Ee et al, 2008), respectively. The isolated terpenoids were also reported most of the Piper species.…”

Section: Resultsmentioning

confidence: 99%

Aporphine alkaloids from Piper erecticaule and acetylcholinesterase inhibitory activity

Salleh¹,

Abdullah²,

Hashim³

et al. 2019

Bol Latinoam Caribe Plant Med Aromat

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Chemical constituents and biological activities of the aerial parts of Piper erecticaule C.DC. have been studied for the first time. Fractionation and purification of the extracts afforded aristolactam AII (1), aristolactam BII (2), piperolactam A (3), piperolactam C (4), piperolactam D (5), together with terpenoids of β-sitosterol, β-sitostenone, taraxerol, and lupeol. The structures of these compounds were obtained by analysis of their spectroscopic data, as well as the comparison with that of reported data. Acetylcholinesterase inhibitory activity revealed that compounds 1 and 3 showed strong AChE inhibitory effects with the percentage inhibition of 75.8% and 74.8%, respectively.Resumen: Se estudiaron por primera vez los constituyentes químicos y actividad biológica de las partes aéreas de Piper erecticaule C.DC. El fraccionamiento y la purificación de los extractos proporcionaron aristolactama AII (1), aristolactama BII (2), piperolactama A (3), piperolactama C (4), piperolactama D (5), junto con terpenoides de β-sitosterol, β-sitostenona, taraxerol, y el lupeol. Las estructuras de estos compuestos se obtuvieron mediante el análisis de sus datos espectroscópicos, así como mediante la comparación con datos ya informados. La actividad inhibidora de la acetilcolinesterasa reveló que los compuestos 1 y 3 mostraron un potente efecto inhibidor de la AChE con un porcentaje de inhibición del 75.8% y 74.8%, respectivamente. Este artículo puede ser citado como / This article must be cited as: WMNHW Salleh, N Abdullah, NA Hashim, HY Khong, S Khamis. 2019 Aporphine alkaloids from Piper erecticaule and acetylcholinesterase inhibitory activity. Bol Latinoam Caribe Plant Med Aromat 18 (5): 527 -532.

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“…In silico analysis. Molecular docking study (Amin et al, 2017a,b, Bhardwaj et al, 2019 was employed to check the binding mode of the investigated compound toward its putative target P2X 7 R. Chem 3D ultra 8.0.3 (Chem 3D Pro Version 8.0 And Chem Draw Ultra Version 8.0) software was used to construct the three-dimensional structure of the investigated compound.…”

Section: Measurement Of P2x7 With Bbgmentioning

confidence: 99%

Spergulin-A strives intra-macrophage leishmanicidal activity by regulating the host P2X₇R-P₃₈MAPK axis

Mukherjee

Banerjee

Amin

et al. 2019

Preprint

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Current drugs are inadequate for the treatment of visceral leishmaniasis an immunosuppressive ailment caused by Leishmania donovani. Regrettably, there is no plant-origin antileishmanial drug present. P2X7R is constitutively present on macrophage surfaces and can be a putative therapeutic target in intra-macrophage pathogens with function attributes towards inflammation, host cell apoptosis, altered redox and phagolysosomal maturation by activating p38MAPK. Here we demonstrated that the initial interaction of Spergulin-A, a triterpenoid saponin with macrophages was mediated through P2X7R involving the signaling cascade intermediates Ca++, P38MAPK, and NF-κβ. P38MAPK involvement shown to have specific and stern importance in leishmanial killing with increased NF-κBp65. Phago-lysosomal maturation by Spergulin-A also campaigns for another contribution of P2X7R. In vivo evaluation of the anti-leishmanial activity of Spergulin-A was monitored through P2X7R, P38MAPK, and NF-κβ in murine spleen and bone-marrow macrophages and advocated Spergulin-A of being a natural compound of leishmanicidal functions which acted through the P2X7R-P38MAPK axis.

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Pharmacoinformatics study of Piperolactam A from Piper betle root as new lead for non steroidal anti fertility drug development

Cited by 27 publications

References 27 publications

Computational Simulations Identified Two Candidate Inhibitors of Cdk5/p25 to Abrogate Tau-associated Neurological Disorders

Computational Simulations Identified Two Candidate Inhibitors of Cdk5/p25 to Abrogate Tau-associated Neurological Disorders

Aporphine alkaloids from Piper erecticaule and acetylcholinesterase inhibitory activity

Spergulin-A strives intra-macrophage leishmanicidal activity by regulating the host P2X₇R-P₃₈MAPK axis

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Pharmacoinformatics study of Piperolactam A from Piper betle root as new lead for non steroidal anti fertility drug development

Cited by 27 publications

References 27 publications

Computational Simulations Identified Two Candidate Inhibitors of Cdk5/p25 to Abrogate Tau-associated Neurological Disorders

Computational Simulations Identified Two Candidate Inhibitors of Cdk5/p25 to Abrogate Tau-associated Neurological Disorders

Aporphine alkaloids from Piper erecticaule and acetylcholinesterase inhibitory activity

Spergulin-A strives intra-macrophage leishmanicidal activity by regulating the host P2X7R-P38MAPK axis

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Product

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Spergulin-A strives intra-macrophage leishmanicidal activity by regulating the host P2X₇R-P₃₈MAPK axis