Screening of selective histone deacetylase inhibitors by proteochemometric modeling.
BACKGROUND
Histone deacetylase (HDAC) is a novel target for the treatment of cancer and it can be classified into three classes, i.e., classes I, II, and IV. The inhibitors selectively targeting individual HDAC have been proved to be the better candidate antitumor drugs. To screen selective HDAC inhibitors, several proteochemometric (PCM) models based on different combinations of three kinds of protein descriptors, two kinds of ligand descriptors and multiplication cross-terms were constructed in our study.


RESULTS
The results show that structure similarity descriptors are better than sequence similarity descriptors and geometry descriptors in the leftacterization of HDACs. Furthermore, the predictive ability was not improved by introducing the cross-terms in our models. Finally, a best PCM model based on protein structure similarity descriptors and 32-dimensional general descriptors was derived (R2 = 0.9897, Qtest2 = 0.7542), which shows a powerful ability to screen selective HDAC inhibitors.


CONCLUSIONS
Our best model not only predict the activities of inhibitors for each HDAC isoform, but also screen and distinguish class-selective inhibitors and even more isoform-selective inhibitors, thus it provides a potential way to discover or design novel candidate antitumor drugs with reduced side effect.
School of Life Sciences and Technology, Tongji University, Shanghai, 200092, PR China.
Dingfeng
D
Wu
Qi
Q
Huang
Yida
Y
Zhang
Qingchen
Q
Zhang
Qi
Q
Liu
Jun
J
Gao
Zhiwei
Z
Cao
Ruixin
R
Zhu
D000970:Antineoplastic Agents / Q000737:chemistry; D004354:Drug Screening Assays, Antitumor / Q000379:methods*; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry*; D006655:Histone Deacetylases / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D009369:Neoplasms / Q000188:drug therapy; D020033:Protein Isoforms / Q000378:metabolism
D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D008024:Ligands; D020033:Protein Isoforms; D006655:Histone Deacetylases