Structural studies of B-type Aurora kinase inhibitors using computational methods

Neaz, M. M.; Muddassar, Muhammad; Pasha, Farhan Ahmad; Cho, Seung Joo

doi:10.1038/aps.2009.188

Cited by 9 publications

(6 citation statements)

References 52 publications

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“…As shown previously in physicochemical parameters, lipophilicity (log P ) seems to be an additional and independent predictive parameter for activity . Thus, correlation of IC 50 values of benzimidazole‐based quinazoline with log P has been expressed in Eq.…”

Section: Resultsmentioning

confidence: 85%

Benzimidazole‐Based Quinazolines: In Vitro Evaluation, Quantitative Structure–Activity Relationship, and Molecular Modeling as Aurora Kinase Inhibitors

Sharma

Luxami

Saxena

et al. 2016

Archiv der Pharmazie

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A series of benzimidazole-based quinazoline derivatives with different substitutions of primary and secondary amines at the C2 position (1-12) were evaluated for their Aurora kinase inhibitory activities. All compounds except for 3 and 6 showed good activity against Aurora kinase inhibitors, with IC50 values in the range of 0.035-0.532 μM. The ligand efficiency (LE) of the compounds with Aurora A kinase was also determined. The structure-activity relationship and the quantitative structure-activity relationship revealed that the Aurora inhibitory activities of these derivatives primarily depend on the different substitutions of the amine present at the C2 position of the quinazoline core. Molecular docking studies in the active binding site also provided theoretical support for the experimental biological data acquired. The current study identifies a novel class of Aurora kinase inhibitors, which can further be used for the treatment of cancer.

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Section: Resultsmentioning

confidence: 85%

Benzimidazole‐Based Quinazolines: In Vitro Evaluation, Quantitative Structure–Activity Relationship, and Molecular Modeling as Aurora Kinase Inhibitors

Sharma

Luxami

Saxena

et al. 2016

Archiv der Pharmazie

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“…where SD is the sum of the squared deviations between the biological activities of the test set and the mean activities of the training molecules and PRESS is the sum of the squared deviation between the predicted and observed activity of the test set molecules [20].…”

Section: Comsia 3d-qsar Modelmentioning

confidence: 99%

“…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: 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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“…However, very few series of Aurora B inhibitors have so far received much attention from a theoretical perspective. More recently, an elegant 3D-QSAR work concerning the quinazoline derivatives of AZD1152 and ZM447439 classes combined with molecular docking was reported [ 24 ]. The authors found the highly active ligands could be designed by varying positively charged, bulky, hydrophobic substitutes at the quinazoline ring, and bulky and hydrophobic groups around the thiazole ring were desirable for higher activity [ 24 ].…”

Section: Introductionmentioning

confidence: 99%

“…More recently, an elegant 3D-QSAR work concerning the quinazoline derivatives of AZD1152 and ZM447439 classes combined with molecular docking was reported [ 24 ]. The authors found the highly active ligands could be designed by varying positively charged, bulky, hydrophobic substitutes at the quinazoline ring, and bulky and hydrophobic groups around the thiazole ring were desirable for higher activity [ 24 ]. More recently, several other series of compounds, such as MK-0457 [ 8 ], GSK1070916 [ 9 ] and SNS-314 [ 4 ] derivatives, have been reported as promising Aurora B inhibitors.…”

Section: Introductionmentioning

confidence: 99%

3D-QSAR and Molecular Docking Studies on Derivatives of MK-0457, GSK1070916 and SNS-314 as Inhibitors against Aurora B Kinase

Zhang

et al. 2010

IJMS

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Development of anticancer drugs targeting Aurora B, an important member of the serine/threonine kinases family, has been extensively focused on in recent years. In this work, by applying an integrated computational method, including comparative molecular field analysis (CoMFA), comparative molecular similarity indices analysis (CoMSIA), homology modeling and molecular docking, we investigated the structural determinants of Aurora B inhibitors based on three different series of derivatives of 108 molecules. The resultant optimum 3D-QSAR models exhibited (q2 = 0.605, r2pred = 0.826), (q2 = 0.52, r2pred = 0.798) and (q2 = 0.582, r2pred = 0.971) for MK-0457, GSK1070916 and SNS-314 classes, respectively, and the 3D contour maps generated from these models were analyzed individually. The contour map analysis for the MK-0457 model revealed the relative importance of steric and electrostatic effects for Aurora B inhibition, whereas, the electronegative groups with hydrogen bond donating capacity showed a great impact on the inhibitory activity for the derivatives of GSK1070916. Additionally, the predictive model of the SNS-314 class revealed the great importance of hydrophobic favorable contour, since hydrophobic favorable substituents added to this region bind to a deep and narrow hydrophobic pocket composed of residues that are hydrophobic in nature and thus enhanced the inhibitory activity. Moreover, based on the docking study, a further comparison of the binding modes was accomplished to identify a set of critical residues that play a key role in stabilizing the drug-target interactions. Overall, the high level of consistency between the 3D contour maps and the topographical features of binding sites led to our identification of several key structural requirements for more potency inhibitors. Taken together, the results will serve as a basis for future drug development of inhibitors against Aurora B kinase for various tumors.

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Structural studies of B-type Aurora kinase inhibitors using computational methods

Cited by 9 publications

References 52 publications

Benzimidazole‐Based Quinazolines: In Vitro Evaluation, Quantitative Structure–Activity Relationship, and Molecular Modeling as Aurora Kinase Inhibitors

Benzimidazole‐Based Quinazolines: In Vitro Evaluation, Quantitative Structure–Activity Relationship, and Molecular Modeling as Aurora Kinase Inhibitors

QSAR studies on imidazopyrazine derivatives as Aurora A kinase inhibitors

3D-QSAR and Molecular Docking Studies on Derivatives of MK-0457, GSK1070916 and SNS-314 as Inhibitors against Aurora B Kinase

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