Farnesyltransferase pharmacophore model derived from diverse classes of inhibitors.
A three-dimensional pharmacophore model was developed based on 25 currently available inhibitors, which were carefully selected with great diversity in both molecular structure and bioactivity as required by HypoGen program in the Catalyst software, for discovering new farnesyltransferase (FTase) inhibitors. The best hypothesis (Hypo1), consisting of four features, namely, two hydrogen-bond acceptors, one hydrophobic point, and one ring aromatic feature, has a correlation coefficient of 0.949, a root-mean-square deviation of 1.321, and a cost difference of 163.15, suggesting that a highly predictive pharmacophore model was successfully obtained. The application of the model shows great success in predicting the activities of 227 known FTase inhibitors in our test set with a correlation coefficient of 0.776 with a cross-validation of 98% confidence level. Accordingly, our model should be reliable in identifying structurally diverse compounds with desired biological activity.
Lu
Aijun
A
JiangSu Simcere Pharmaceutical Research Company Ltd. 210042 Nanjing, China.
Zhang
Jian
J
Yin
Xiaojin
X
Luo
Xiaomin
X
Jiang
Hualiang
H
D000970:Antineoplastic Agents / Q000737:chemistry*; D004791:Enzyme Inhibitors / Q000737:chemistry*; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors*; D008956:Models, Chemical; D015394:Molecular Structure; D012984:Software; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D051231:Farnesyltranstransferase