Molecular modelling evaluation of the cytotoxic activity of podophyllotoxin analogues

Alam, Md. Afroz; Naik, Pradeep Kumar

doi:10.1007/s10822-008-9252-1

Cited by 13 publications

(2 citation statements)

References 34 publications

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“…Tubulin polymerization inhibitors have also become an effective class of anti-tumor drugs. 10 This class of inhibitors destroys the microtubules by inhibiting the polymerization of tubulin or promoting the polymerization of tubulin, interfering with the mitosis process of cells, thereby exerting anti-tumor effects. 11,12 At present, microtubule polymerization inhibitors include colchicine and vinblastine.…”

Section: Introductionmentioning

confidence: 99%

Discovery of novel tubulin polymerization inhibitors by utilizing 3D-QSAR, molecular docking and molecular dynamics simulation

Zhao

Zhang

et al. 2022

New J. Chem.

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Section: Introductionmentioning

confidence: 99%

Discovery of novel tubulin polymerization inhibitors by utilizing 3D-QSAR, molecular docking and molecular dynamics simulation

Zhao

Zhang

et al. 2022

New J. Chem.

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“…Worldwide, Chronic kidney disease (CKD) is a major public health problem; it is one of the high-risk factors for hypertension and diabetes [ 1 ] patients. Progressive reduction of circulating 1α,25-dihydroxy vitamin D 3 (1α, 25(OH) 2 D 3 ) and 25-hydroxyvitamin D 3 (25(OH) 2 D 3 ) are common expression variation observed in CKD patients [ 2 ].…”

Section: Introductionmentioning

confidence: 99%

A theoretical insight to understand the molecular mechanism of dual target ligand CTA-018 in the chronic kidney disease pathogenesis

Nagamani

Muthusamy

2018

PLoS ONE

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The level of the vitamin D in the bloodstream is regulated by cytochrome P450 enzyme 24-hydroxylase A1 (CYP24A1). Over expression of CYP24A1 enzyme is correlated with vitamin D deficiency and resistance to vitamin D therapy. Chronic kidney disease (CKD) patients are commonly reported with the above said expression variations. This deregulation could be solved by ligands that act as a vitamin D receptor (VDR) agonists and CYP24A1 antagonists. Posner et al., (2010) first time reported two new vitamin D analogues namely CTA-091 and CTA-018 to inhibit CYP24A1. The CTA-018 inhibited CYP24A1 with an IC50 27 ± 6 nM (10 times more potent than the ketoconazole (253 ± 20 nM)). CTA-018 induced VDR expression (15-fold lower than 1α,25(OH)2D3) and is under phase II clinical trial, whereas CTA-091 was not able to efficiently induce the VDR expression (>2000 nM). To explore the molecular mechanism, binding specificity of these two vitamin D analogues along with native ligand was extensively studied through in silico approaches. Through molecular dynamics simulations studies, we shown that the sulfonic group (O = S = O) in the side chain of CTA-018 plays an important role in the regulation of VDR agonistic activity. The electron lone pairs of the sulfonic group that interacted with His393 lead to be a factor for agonistic mechanism of VDR activity. Compared to azol-based compounds, CTA-018 binds the different sites in the CYP24A1 binding cavity and thus it could be a potent antagonistic for CYP24A1enzyme.

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Rational design, synthesis and biological evaluations of amino-noscapine: a high affinity tubulin-binding noscapinoid

Naik

Chatterji

Vangapandu

et al. 2011

J Comput Aided Mol Des

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Noscapine and its derivatives are important microtubule-interfering agents shown to have potent anti-tumor activity. The binding free energies (ΔG (bind)) of noscapinoids computed using linear interaction energy (LIE) method with a surface generalized Born (SGB) continuum solvation model were in agreement with the experimental ΔG (bind) with average root mean square error of 0.082 kcal/mol. This LIE-SGB model guided us in designing a novel derivative of noscapine, amino-noscapine [(S)-3-((R)-9-amino-4-methoxy-6-methyl-5,6,7,8-tetrahydro [1, 3] dioxolo[4,5-g]isoquinolin-5-yl)-6,7-dimethoxy isobenzo-furan-1(3H)-one] that has higher tubulin binding activity (predicted ΔG (bind) = -6.438 kcal/mol and experimental ΔG (bind) = -6.628 kcal/mol) than noscapine, but does not significantly change the total extent of the tubulin subunit/polymer ratio. The modes of interaction of amino-noscapine with the binding pocket of tubulin involved three hydrogen bonds and are distinct compared to noscapine which involved only one hydrogen bond. Also the patterns of non-bonded interactions are albeit different between both the lignads. The 'blind docking' approach (docking of ligand with different binding sites of a protein and their evaluations) as well as the reasonable accuracy of calculating ΔG (bind) using LIE-SGB model constitutes the first evidence that this class of compounds binds to tubulin at a site overlapping with colchicine-binding site or close to it. Our results revealed that amino-noscapine has better anti-tumor activity than noscapine.

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Molecular modelling evaluation of the cytotoxic activity of podophyllotoxin analogues

Cited by 13 publications

References 34 publications

Discovery of novel tubulin polymerization inhibitors by utilizing 3D-QSAR, molecular docking and molecular dynamics simulation

Discovery of novel tubulin polymerization inhibitors by utilizing 3D-QSAR, molecular docking and molecular dynamics simulation

A theoretical insight to understand the molecular mechanism of dual target ligand CTA-018 in the chronic kidney disease pathogenesis

Rational design, synthesis and biological evaluations of amino-noscapine: a high affinity tubulin-binding noscapinoid

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