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3D-QSAR of histone deacetylase inhibitors: hydroxamate analogues.
Org Biomol Chem. 2006 Aug 07; 4(15):2858-68.OB

Abstract

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 r(2)(conv), r(2)(cv) and r(2)(pred). In addition to steric and electronic fields, ClogP was also taken as descriptor to account for lipophilicity. The resulting models exhibited a good conventional r(2)(conv) and cross-validated r(2)(cv) 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.

Authors+Show Affiliations

Juvale DC
Poona College of Pharmacy, Bharati Vidyapeeth Deemed University, Erandwane, Pune, India.
Kulkarni VV
No affiliation info available
Deokar HS
No affiliation info available
Wagh NK
No affiliation info available
Padhye SB
No affiliation info available
Kulkarni VM
No affiliation info available

MeSH

Enzyme InhibitorsHistone Deacetylase InhibitorsHydroxamic AcidsModels, MolecularQuantitative Structure-Activity Relationship

Pub Type(s)

Journal Article

Language

eng

PubMed ID

16855733

Citation

Juvale, Dhanshri C., et al. "3D-QSAR of Histone Deacetylase Inhibitors: Hydroxamate Analogues." Organic & Biomolecular Chemistry, vol. 4, no. 15, 2006, pp. 2858-68.
Juvale DC, Kulkarni VV, Deokar HS, et al. 3D-QSAR of histone deacetylase inhibitors: hydroxamate analogues. Org Biomol Chem. 2006;4(15):2858-68.
Juvale, D. C., Kulkarni, V. V., Deokar, H. S., Wagh, N. K., Padhye, S. B., & Kulkarni, V. M. (2006). 3D-QSAR of histone deacetylase inhibitors: hydroxamate analogues. Organic & Biomolecular Chemistry, 4(15), 2858-68.
Juvale DC, et al. 3D-QSAR of Histone Deacetylase Inhibitors: Hydroxamate Analogues. Org Biomol Chem. 2006 Aug 7;4(15):2858-68. PubMed PMID: 16855733.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 3D-QSAR of histone deacetylase inhibitors: hydroxamate analogues. AU - Juvale,Dhanshri C, AU - Kulkarni,Vishal V, AU - Deokar,Hemantkumar S, AU - Wagh,Nilesh K, AU - Padhye,Subhash B, AU - Kulkarni,Vithal M, Y1 - 2006/06/27/ PY - 2006/7/21/pubmed PY - 2006/9/21/medline PY - 2006/7/21/entrez SP - 2858 EP - 68 JF - Organic & biomolecular chemistry JO - Org Biomol Chem VL - 4 IS - 15 N2 - 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 r(2)(conv), r(2)(cv) and r(2)(pred). In addition to steric and electronic fields, ClogP was also taken as descriptor to account for lipophilicity. The resulting models exhibited a good conventional r(2)(conv) and cross-validated r(2)(cv) 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. SN - 1477-0520 UR - https://www.unboundmedicine.com/medline/citation/16855733/3D_QSAR_of_histone_deacetylase_inhibitors:_hydroxamate_analogues_ L2 - https://doi.org/10.1039/b606365a DB - PRIME DP - Unbound Medicine ER -