Molecular docking/dynamics studies of Aurora A kinase inhibitors

Talele, Tanaji T.; McLaughlin, Mark L.

doi:10.1016/j.jmgm.2007.11.003

Cited by 34 publications

(24 citation statements)

References 29 publications

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“…The grids were generated using bound rUTP with the default parameters. The Glide docking program v5.5 (Schrodinger, LLC, New York, NY) was used to dock the conformational library of each ligand as per the details described in our previous studies [24, 34]. …”

Section: Methodsmentioning

confidence: 99%

Synthesis and SAR optimization of diketo acid pharmacophore for HCV NS5B polymerase inhibition

Bhatt

Gurukumar

Basu

et al. 2011

European Journal of Medicinal Chemistry

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Hepatitis C virus (HCV) NS5B polymerase is a key target for anti-HCV therapeutics development. Here we report the synthesis and biological evaluation of a new series of α,γ-diketo acids (DKAs) as NS5B polymerase inhibitors. We initiated structure-activity relationship (SAR) optimization around the furan moiety of compound 1a [IC50 = 21.8 μM] to achieve more active NS5B inhibitors. This yielded compound 3a [IC50 = 8.2 μM] bearing the 5-bromobenzofuran-2-yl moiety, the first promising lead compound of the series. Varying the furan moiety with thiophene, thiazole and indazole moieties resulted in compound 11a [IC50 = 7.5 μM] bearing 3-methylthiophen-2-yl moiety. Finally replacement of the thiophene ring with a bioisosteric phenyl ring further improved the inhibitory activity as seen in compounds 21a [IC50 = 5.2 μM] and 24a [IC50 = 2.4 μM]. Binding mode of compound 24a using glide docking within the active site of NS5B polymerase will form the basis for future SAR optimization.

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Section: Methodsmentioning

confidence: 99%

Synthesis and SAR optimization of diketo acid pharmacophore for HCV NS5B polymerase inhibition

Bhatt

Gurukumar

Basu

et al. 2011

European Journal of Medicinal Chemistry

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“…Figure 6 revealed the relative positions of the two inhibitors and correlated residues in the binding pocket by the lowest energy structure extracted from the last 100 ns MD trajectories. In addition, hydrogen bond interaction has been con¯rmed to play an important role in ligand binding, 17,61À65 the intermolecular hydrogen bond analyses based on the last 100 ns MD simulations were also performed ( Table 2).…”

Section: Binding Mode Of the Aurora Aàinhibitor Complexmentioning

confidence: 99%

Understanding the Molecular Mechanism of Binding Modes of Aurora a Inhibitors by Long Time Scale Gpu Dynamics

Xiu

et al. 2013

J. Theor. Comput. Chem.

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Inhibition of Aurora A kinase interaction is considered to be a promissing approach for the discovery of new molecularly targeted cancer therapeutics. In this study, the binding mechanisms of two di®erent inhibitors with a contrasting binding a±nity to Aurora A were investigated by long time scale GPU molecular dynamics (MD) simulations coupled with molecular mechanics-PoissonÀBoltzmann/generalized Born surface area (MM-PB/GBSA) method. The results showed that the predicted binding free energies of these two complexes were consistent with the experimental data. Through analyzing the individual energy components of binding free energy, we found that the van der Waals contribution was the main force to drive the inhibitorÀprotein binding and the electrostatic contribution was also a crucial factor for the inhibitorÀAurora A binding. The structural analysis demonstrated that the inhibitor HPM could produce more hydrophobic interaction contacts with Aurora A than that of 2JZ, and the loss of key hydrogen bonds between the inhibitor and residue Arg137 in the hinge region of † † Corresponding authors.

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“…of Aurora A kinase [21]. One of the most important considerations in docking simulations was the selection of an appropriate docking algorithm.…”

Section: Structure-based Ligand Docking Analysismentioning

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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Molecular docking/dynamics studies of Aurora A kinase inhibitors

Cited by 34 publications

References 29 publications

Synthesis and SAR optimization of diketo acid pharmacophore for HCV NS5B polymerase inhibition

Synthesis and SAR optimization of diketo acid pharmacophore for HCV NS5B polymerase inhibition

Understanding the Molecular Mechanism of Binding Modes of Aurora a Inhibitors by Long Time Scale Gpu Dynamics

QSAR studies on imidazopyrazine derivatives as Aurora A kinase inhibitors

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