title: 3D-QSAR studies of HDACs inhibitors using pharmacophore-based alignment.
abstract: Histone deacetylases (HDACs) enzyme is a promising target for the development of anticancer drugs. The enzyme-bound conformation of Trichostatin A (TSA) (PDB ID:1C3R) as an inhibitor of HDACs was used to manually construct a pharmacophore model. This model was then successfully used to identify the bioactive conformation and align flexible and structurally diverse molecules. Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were performed on hydroxamate-based HDACs inhibitors based on phamacophore alignment. The best predictions were obtained with CoMFA standard model (q(2) = 0.726, r(2) = 0.998) and CoMSIA model combined with steric, electrostatic, hydrophobic, hydrogen bond donor and acceptor fields (q(2) = 0.610, r(2) = 0.995). Both of the models were validated by an external test set, which gave a satisfactory predictive r(2) value of 0.800 and 0.732, respectively. Graphical interpretation of the results revealed important structural features of the inhibitors related to the active site of HDACs. The results may be exploited for further design and virtual screening for some novel HDACs inhibitors.
authors.affiliation: Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, PR China.
authors.forename: Yadong
authors.initials: Y
authors.lastname: Chen
authors.forename: Huifang
authors.initials: H
authors.lastname: Li
authors.forename: Wanquan
authors.initials: W
authors.lastname: Tang
authors.forename: Chengchao
authors.initials: C
authors.lastname: Zhu
authors.forename: Yongjun
authors.initials: Y
authors.lastname: Jiang
authors.forename: Jianwei
authors.initials: J
authors.lastname: Zou
authors.forename: Qingsen
authors.initials: Q
authors.lastname: Yu
authors.forename: Qidong
authors.initials: Q
authors.lastname: You
mesh_terms: D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D008024:Ligands; D008958:Models, Molecular; D017434:Protein Structure, Tertiary; D021281:Quantitative Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D008024:Ligands; C012589:trichostatin A; D006655:Histone Deacetylases