@article{APS7972,
author = {Miao-miao NIU and Jing-yi QIN and Cai-ping TIAN and Xia-fei YAN and Feng-gong DONG and Zheng-qi CHENG and Guissi FIDA and Man YANG and Haiyan CHEN and Yue-qing GU},
title = {Tubulin inhibitors: pharmacophore modeling, virtual screening and molecular docking},
journal = {Acta Pharmacologica Sinica},
volume = {35},
number = {7},
year = {2016},
keywords = {},
abstract = {Miao-miao NIU#, Jing-yi QIN#, Cai-ping TIAN, Xia-fei YAN, Feng-gong DONG, Zheng-qi CHENG, Guissi FIDA, Man YANG, Hai-yan CHEN, Yue-qing GU*
Department of Biomedical Engineering, School of Life Science and Technology, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
Aim: To construct a quantitative pharmacophore model of tubulin inhibitors and to discovery new leads with potent antitumor activities.
Methods: Ligand-based pharmacophore modeling was used to identify the chemical features responsible for inhibiting tubulin polymerization. A set of 26 training compounds was used to generate hypothetical pharmacophores using the HypoGen algorithm. The structures were further validated using the test set, Fischer randomization method, leave-one-out method and a decoy set, and the best model was chosen to screen the Specs database. Hit compounds were subjected to molecular docking study using a Molecular Operating Environment (MOE) software and to biological evaluation in vitro.
Results: Hypo1 was demonstrated to be the best pharmacophore model that exhibited the highest correlation coefficient (0.9582), largest cost difference (70.905) and lowest RMSD value (0.6977). Hypo1 consisted of one hydrogen-bond acceptor, a hydrogen-bond donor, a hydrophobic feature, a ring aromatic feature and three excluded volumes. Hypo1 was validated with four different methods and had a goodness-of-hit score of 0.81. When Hypo1 was used in virtual screening of the Specs database, 952 drug-like compounds were revealed. After docking into the colchicine-binding site of tubulin, 5 drug-like compounds with the required interaction with the critical amino acid residues and the binding free energies },
issn = {1745-7254}, url = {http://www.chinaphar.com/article/view/7972}
}