Molecular modeling studies on imidazo[4,5-b]pyridine derivatives as Aurora A kinase inhibitors using 3D-QSAR and docking approaches

Lan, Ping; Chen, Wan-Na; Chen, Weimin

doi:10.1016/j.ejmech.2010.10.017

Cited by 42 publications

(17 citation statements)

References 41 publications

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“…The Van Der Waals potentials and Coulombic terms, which represent steric and electrostatic fields, respectively, were calculated by using the standard Tripos force field. In the CoMFA method, a sp 3 hybridized carbon atom with a charge of 1e was used as a probe atom, the energy values of the steric and electrostatic fields were truncated at 30 kcal/mol [21]. …”

Section: Methodsmentioning

confidence: 99%

Combined 3D-QSAR Modeling and Molecular Docking Studies on Pyrrole-Indolin-2-ones as Aurora A Kinase Inhibitors

Wang

Sun

et al. 2011

IJMS

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Aurora kinases have emerged as attractive targets for the design of anticancer drugs. 3D-QSAR (comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA)) and Surflex-docking studies were performed on a series of pyrrole-indoline-2-ones as Aurora A inhibitors. The CoMFA and CoMSIA models using 25 inhibitors in the training set gave r2cv values of 0.726 and 0.566, and r2 values of 0.972 and 0.984, respectively. The adapted alignment method with the suitable parameters resulted in reliable models. The contour maps produced by the CoMFA and CoMSIA models were employed to rationalize the key structural requirements responsible for the activity. Surflex-docking studies revealed that the sulfo group, secondary amine group on indolin-2-one, and carbonyl of 6,7-dihydro-1H-indol-4(5H)-one groups were significant for binding to the receptor, and some essential features were also identified. Based on the 3D-QSAR and docking results, a set of new molecules with high predicted activities were designed.

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Section: Methodsmentioning

confidence: 99%

Combined 3D-QSAR Modeling and Molecular Docking Studies on Pyrrole-Indolin-2-ones as Aurora A Kinase Inhibitors

Wang

Sun

et al. 2011

IJMS

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“…In our work, the most active compound 27, was used as a template for alignment, and the common fragment of 65 compounds is shown in Figure 1(A). The compound 27 was used as the template for alignment, and the rest of compounds were aligned on it [12]. This process was performed by Database Align of SYBYL 7.3.…”

Section: Methodsmentioning

confidence: 99%

Combined 3D-QSAR and Docking Modelling Study on Indolocarbazole Series Compounds as Tie-2 Inhibitors

Tian

et al. 2011

IJMS

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Tie-2, a kind of endothelial cell tyrosine kinase receptor, is required for embryonic blood vessel development and tumor angiogenesis. Several compounds that showed potent activity toward this attractive anticancer drug target in the assay have been reported. In order to investigate the structure-activity correlation of indolocarbazole series compounds and modify them to improve their selectivity and activity, 3D-QSAR models were built using CoMFA and CoMSIA methods and molecular docking was used to check the results. Based on the common sketch align, two good QSAR models with high predictabilities (CoMFA model: q2 = 0.823, r2 = 0.979; CoMSIA model: q2 = 0.804, r2 = 0.967) were obtained and the contour maps obtained from both models were applied to identify the influence on the biological activity. Molecular docking was then used to confirm the results. Combined with the molecular docking results, the detail binding mode between the ligands and Tie-2 was elucidated, which enabled us to interpret the structure-activity relationship. These satisf actory results not only offered help to comprehend the action mechanism of indolocarbazole series compounds, but also provide new information for the design of new potent inhibitors.

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“…The cyan regions, which were observed near the first position of the pyrazole ring and C8-NH groups in the imidazo [1, 2-a] pyrazine core, may increase the activity of the inhibitors, thus compounds (18,19,20,21,36, 37) without a potential hydrogen bond donor at the first position of the pyrazole ring show low activity. The purple regions were observed near the thiophene ring and sulphamide substituting group, contributing to the lower activity of these molecules, such as compound 2, compound 5 and compound 13.…”

Section: Sar and Qsar In Environmental Research 15mentioning

confidence: 97%

“…Molecular similarity was expressed in terms of five different properties, including steric, electrostatic, hydrophobic, H-bond donors and H-bond acceptors, which was calculated at each lattice intersection of a regularly spaced grid of 1 Å and extending to 4 Å using a sp 3 hybridized carbon as probe atom with charge þ1, radius 1 Å , hydrophobicity þ1, and attenuation factor of 0.3 for the Gaussian type distance [15,18].…”

Section: Comsia 3d-qsar Modelmentioning

confidence: 99%

QSAR studies on imidazopyrazine derivatives as Aurora A kinase inhibitors

Liu

Lü

Yuan

et al. 2012

SAR and QSAR in Environmental Research

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Aurora kinases have emerged as attractive targets for the development of novel anti-cancer agents. A combined study of molecular docking, pharmacophore modelling and 3D-QSAR was performed on a series of imidazo [1, 2-a] pyrazines as novel Aurora kinase inhibitors to gain insights into the structural determinants and their structure-activity relationship. An ensemble of conformations based on molecular docking was used for PHASE pharmacophore studies. The developed best-fitted pharmacophore model was validated by diverse chemotypes of Aurora A kinase inhibitors and was consistent with the structural requirements for the docked binding mechanism. Subsequently, the pharmacophore-based alignment was used to develop PHASE and comparative molecular similarity indices analysis (CoMSIA) 3D-QSAR models. The best CoMSIA model showed good statistics (q (2 )= 0.567, r (2 )= 0.992), and the predictive ability of the model was validated using an external test set of 13 compounds giving a satisfactory prediction ([Formula: see text]). The 3D contour maps provided insight into the binding mechanism and highlighted key structural features that are essential to the inhibitory activity. Based on the PHASE and CoMSIA 3D-QSAR results, a set of novel Aurora A inhibitors were designed that showed excellent potencies.

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Molecular modeling studies on imidazo[4,5-b]pyridine derivatives as Aurora A kinase inhibitors using 3D-QSAR and docking approaches

Cited by 42 publications

References 41 publications

Combined 3D-QSAR Modeling and Molecular Docking Studies on Pyrrole-Indolin-2-ones as Aurora A Kinase Inhibitors

Combined 3D-QSAR Modeling and Molecular Docking Studies on Pyrrole-Indolin-2-ones as Aurora A Kinase Inhibitors

Combined 3D-QSAR and Docking Modelling Study on Indolocarbazole Series Compounds as Tie-2 Inhibitors

QSAR studies on imidazopyrazine derivatives as Aurora A kinase inhibitors

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