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3D-QSAR of histone deacetylase inhibitors: hydroxamate analogues

2006; Royal Society of Chemistry; Volume: 4; Issue: 15 Linguagem: Inglês

10.1039/b606365a

1477-0539

Dhanshri C. Juvale, Vishal Vithalrao Kulkarni, Hemantkumar Deokar, Nilesh Wagh, Subhash Padhyé, Vithal M. Kulkarni,

Catalytic C–H Functionalization Methods

The histone deacetylase enzyme has increasingly become an attractive target for developing novel anticancer drugs. Hydroxamates are a new class of anticancer agents reported to act by selective inhibition of the histone deacetylase (HDAC) enzyme. Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were employed to study three-dimensional quantitative structure–activity relationships (3D-QSARs). QSAR models were derived from a training set of 40 molecules. An external test set consisting of 17 molecules was used to validate the CoMFA and CoMSIA models. All molecules were superimposed on the template structure by atom-based, multifit and the SYBYL QSAR rigid body field fit alignments. The statistical quality of the QSAR models was assessed using the parameters r2conv, r2cv and r2pred. In addition to steric and electronic fields, ClogP was also taken as descriptor to account for lipophilicity. The resulting models exhibited a good conventional r2conv and cross-validated r2cv values up to 0.910 and 0.502 for CoMFA and 0.987 and 0.534 for CoMSIA. Robust cross-validation by 2 groups was performed 25 times to eliminate chance correlation. The CoMFA models exhibited good external predictivity as compared to that of CoMSIA models. These 3D-QSAR models are very useful for design of novel HDAC inhibitors.