Exploring the selectivity of a ligand complex with CDK2/CDK1: a molecular dynamics simulation approach

Tripathi, Sunil Kumar; Singh, Poonam; Palanisamy, Chella Perumal; Reddy, Karnati Konda; Selvaraj, Chandrabose

doi:10.1002/jmr.2216

Cited by 45 publications

(28 citation statements)

References 81 publications

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“…The binding site residues of HER2, EGFR and CXCR2 produced hydrophobic, hydrophilic maps and hydrogen binding possibilities which may guide the protein-ligand docking analysis (Tripathi et al, 2012). In order to rationalize the described structure characterization, protein preparation and site map prediction results, molecular docking studies were undertaken on epifriedelanol (isolated compound) and carboplatin (FDA approved drug for ovarian cancer) complexes with X-Ray crystal structure of HER2, EGFR and CXCR2 (ovarian cancer targets).…”

Section: Discussionmentioning

confidence: 99%

Assessment of dual inhibitory activity of epifriedelanol isolated from Cayratia trifolia against ovarian cancer

Palanisamy

Sowmya

Velmurugan

et al. 2016

Bangladesh J Pharmacol

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Cayratia trifolia is used as diuretic, in tumors, neuralgia and splenopathy. However, compounds depicting anti-ovarian cancer activities from this plant source have not yet been identified and structurally characterized till date. In the present study, X-ray structure of epifriedelanol, a bioactive compound, isolated from the ethanolic extract of the C. trifolia and its binding affinities against a few proteins (HER2, EGFR and CXCR4) that are reported to get overexpressed under ovarian cancer had been thoroughly studied by using molecular docking means. Binding affinities of the compound vis-à-vis that of carboplatin, a FDA approved drug to the ovarian cancer, to interact with the protein targets are quite impressive. The drug-likeness properties of the epifriedelanol and scope to develop the compound as a potent anti-ovarian cancer drug are discussed in this paper.

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Section: Discussionmentioning

confidence: 99%

Assessment of dual inhibitory activity of epifriedelanol isolated from Cayratia trifolia against ovarian cancer

Palanisamy

Sowmya

Velmurugan

et al. 2016

Bangladesh J Pharmacol

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“…With the rapid development of homology modeling methodology, it provides us an alternative way to study from the structure-based point of view. Structures are built based on templates by homology modeling for proteins without dissolved crystal structure (Gallina et al, 2014;Thomas et al, 2014;Tripathi et al, 2012). Besides, homology modeling method provides the opportunities for identifying potential agonists or antagonist by structure-based virtual screening (Pala et al, 2013;Tarcsay et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

A selectivity study of sodium-dependent glucose cotransporter 2/sodium-dependent glucose cotransporter 1 inhibitors by molecular modeling

Yuan²,

Ran

et al. 2015

J. Mol. Recognit.

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Sodium-dependent glucose cotransporters (SGLTs) play an important role in glucose reabsorption in the kidney and have been identified as promising targets to treat diabetes. Because of the side effects like glucose and galactose malabsorption by targeting SGLT1, highly selective SGLT2 inhibitors are more promising in the treatment of diabetes. To understand the mechanism of selectivity, we conducted selectivity-based three-dimensional quantitative structure-activity relationship studies to highlight the structure requirements for highly selective SGLT2 inhibitors. The best comparative molecular field analysis and comparative molecular similarity indices analysis models showed the noncross-validated coefficient (r(2) ) of 0.967 and 0.943, respectively. The predicted correlation coefficients (r(2) pred ) of 0.974 and 0.938 validated the reliability and predictability of these models. Besides, homology models of SGLT2 and SGLT1 were also constructed to investigate the selective mechanism from structure-based perspective. Molecular dynamics simulation and binding free energy calculation were performed on the systems of a potent and selective compound interacting with SGLT2 and SGLT1 to compare the different binding modes. The simulation results showed that the stretch of the methylthio group on Met241 had an essential effect on the different binding modes between SGLT1 and SGLT2, which was consistent with the three-dimensional quantitative structure-activity relationship analysis. Hydrogen bond analysis and binding free energy calculation revealed that SGLT2 binding complex was more stable and favorable than SGLT1 complex, which was highly correlated with the experimental results. Our obtained results give useful information for the investigation of the inhibitors' selectivity between SGLT2 and SGLT1 and will help for further development of highly selective SGLT2 inhibitors.

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“…found that Leu83 is a key residue that recognizes BS194 more effectively with CDK2 with good binding free energies rather than CDK1. Energetic analysis reveals that van der Waals interaction and nonpolar contributions to solvent are favorable in formation of complexes and amine group of the ligand, which plays a crucial role for binding selectivity between CDK2 and CDK1 . Aixiao et al .…”

Section: Resultsmentioning

confidence: 99%

Comparative Analysis of Various Electrostatic Potentials on Docking Precision Against Cyclin‐Dependent Kinase 2 Protein: A Multiple Docking Approach

2014

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The fundamental of molecular modeling is the interaction and binding to form a complex, because it explains the action of most drugs to a receptor active site. In the present study, different semiempirical (RM1, AM1, PM3, MNDO) and ab initio (HF, DFT) charge models were investigated for their performance in prediction of docking pose against CDK2 proteins with their respective inhibitor. Further, multiple docking approaches and Prime/MM-GBSA calculations were applied to predict the binding mode with respective charge model against CDK2 inhibitors. A reliable docking result was obtained using RRD, which showed significance improvement on ligand binding poses and docking score accuracy to the IFD. The combined use of RRD and Prime/MM-GBSA method could give a high correlation between the predicted binding free energy and experimental biological activity. The preliminary results point out that AM1 could be a precious charge model for design of new drugs with enhanced success rate. As a very similar result was also found for a different system of the protein-ligand binding, the suggested scoring function based on AM1 method seems to be applicable in drug design. The results from this study can provide insights into highest success rate for design of potent and selective CDK2 inhibitors.

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Exploring the selectivity of a ligand complex with CDK2/CDK1: a molecular dynamics simulation approach

Cited by 45 publications

References 81 publications

Assessment of dual inhibitory activity of epifriedelanol isolated from <i>Cayratia trifolia</i> against ovarian cancer

Assessment of dual inhibitory activity of epifriedelanol isolated from <i>Cayratia trifolia</i> against ovarian cancer

A selectivity study of sodium-dependent glucose cotransporter 2/sodium-dependent glucose cotransporter 1 inhibitors by molecular modeling

Comparative Analysis of Various Electrostatic Potentials on Docking Precision Against Cyclin‐Dependent Kinase 2 Protein: A Multiple Docking Approach

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