Computational identification of novel histone deacetylase inhibitors by docking based QSAR

Nair, Syam; Teli, Mahesh Kumar; Pradeep, H.; Rajanikant, G. K.

doi:10.1016/j.compbiomed.2012.04.001

Cited by 37 publications

(23 citation statements)

References 24 publications

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“…The potential hit compounds with lowest RMSD and standard molecular weights were considered for the docking analysis. All the hits were subjected to hydrogen additions, removal of salt, ionization and generation of low-energy ring conformations using LigPrep [37,38]. The tautomers for each of these ligands were generated and optimized.…”

Section: Docking Methodologymentioning

confidence: 99%

A rational approach to selective pharmacophore designing: an innovative strategy for specific recognition of Gsk3β

Pradeep

Rajanikant

2012

Mol Divers

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We propose a novel cheminformatics approach that combines structure and ligand-based design to identify target-specific pharmacophores with well-defined exclusion ability. Our strategy includes the prediction of selective interactions, developing structure, and knowledge-based selective pharmacophore models, followed by database screening and molecular docking. This unique strategy was employed in addressing the off-target toxicity of Gsk3β and CDKs. The connections of Gsk3β in eukaryotic cell apoptosis and the extensive potency of Gsk3β inhibitors to block cell death have made it a potential drug-discovery target for many grievous human disorders. Gsk3β is phylogenetically very closely related to the CDKs, such as CDK1 and CDK2, which are suggested to be the off-target proteins of Gsk3β inhibitors. Here, we have employed novel computational approaches in designing the ligand candidates that are potentially inhibitory against Gsk3β, with well-defined the exclusion ability to CDKs. A structure-ligand -based selective pharmacophore was modeled. This model was used to retrieve molecules from the zinc database. The hits retrieved were further screened by molecular docking and protein-ligand interaction fingerprints. Based on these results, four molecules were predicted as selective Gsk3β antagonists. It is anticipated that this unique approach can be extended to investigate any protein-ligand specificity.

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Section: Docking Methodologymentioning

confidence: 99%

A rational approach to selective pharmacophore designing: an innovative strategy for specific recognition of Gsk3β

Pradeep

Rajanikant

2012

Mol Divers

Self Cite

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“…This model, as shown in Figure 26 with its distance constraints, was mapped to the most and the least active compounds of the training set (14 and 15 with IC 50 = 0.02 nM and 1500 μM, respectively) ( Figure 27). Nair et al 153 had proposed a pharmacophore model (AAAPR) that consisted of five structural features: three Hbond acceptors (AAA), one positive ionic group (P), and one aromatic feature (R).…”

Section: Hdac Inhibitionmentioning

confidence: 99%

QSAR Studies on Hydroxamic Acids: A Fascinating Family of Chemicals with a Wide Spectrum of Activities

Gupta

2015

Chem. Rev.

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“…Lastly, these PHASE generated pharmacophore-based alignment was utilized for the development of QSAR model (Dixon et al, 2006). A lot of pharmacophore model thus generated with PHASE were used widely to find out novel lead compounds and utilized in ligand discovery (Telvekar and Chaudhari, 2012; Reddy et al, 2012;Nair et al, 2012;Nagamani et al, 2012;Mehta et al, 2012;Guasch et al, 2012;Sun et al, 2011;Almerico et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Atom-based QSAR and 3D QSAR using pharmacophore based alignment for discovery of nimesulide-derived SKBR-3 cell line inhibitors

Choudhury

2014

Med Chem Res

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Growth suppression of many non-COX-2 expressing tumor cells can be exhibited by COX-2 inhibitors, where supplementation of cells with exogenous prostaglandins fails to rescue the cells from growth inhibition. It can, therefore, be speculated that anti-cancer properties of some COX-2 inhibitors may be contributed by the COX-2-independent effects also. Some of the derivatives obtained from certain COX-2 inhibitors which show non-COX-2 inhibitory mechanism have revealed some significant anti-cancer activities. From a COX-2 selective inhibitor nimesulide, an analog JCC76 is derived which is a non-COX-2 active compound and shows inhibition of SKBR-3 breast cancer cell growth. Other JCC76 derived inhibitors also played significant role in SKBR-3 cell inhibition. An analog-based study was done using pharmacophore modeling and 3D-QSAR to provide clues for potential lead compound designing. A five point pharmacophore ADHRR was generated using 39 JCC76-derived SKBR-3 inhibitors. The validated pharmacophore alignment was used for further 3D-QSAR analysis, which presented a good R 2 value of 0.562, 0.982, and 0.848 for atombased QSAR, CoMFA, and CoMSIA model, respectively. All the QSAR models presented good statistical significance and predictivity. The corresponding Q 2 values for each model are 0.513, 0.649, and 0.518, respectively. Both the pharmacophore and CoMSIA results displayed that the H-bond donor and acceptor sites are the key structural feature for JCC76-derived non-COX-2-dependent inhibitors with high activity.

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Computational identification of novel histone deacetylase inhibitors by docking based QSAR

Cited by 37 publications

References 24 publications

A rational approach to selective pharmacophore designing: an innovative strategy for specific recognition of Gsk3β

A rational approach to selective pharmacophore designing: an innovative strategy for specific recognition of Gsk3β

QSAR Studies on Hydroxamic Acids: A Fascinating Family of Chemicals with a Wide Spectrum of Activities

Atom-based QSAR and 3D QSAR using pharmacophore based alignment for discovery of nimesulide-derived SKBR-3 cell line inhibitors

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