Understanding the antitumor activity of novel tricyclicpiperazinyl derivatives as farnesyltransferase inhibitors using CoMFA and CoMSIA.
3D-QSAR studies of some tricyclicpiperazinyl derivatives as farnesyltransferase inhibitors were performed by comparative molecular field analysis (CoMFA) and comparative molecular similarity indices (CoMSIA) methods to rationalize the structural requirements responsible for the inhibitory activity of these compounds. The global minimum energy conformer of the template molecule 35, the most active and pharmacokinetically stable molecule of the series, was obtained by simulated annealing method and used to build structures of the molecules in the dataset. The CoMFA model obtained after the removal of outliers produced statistically significant results with cross-validated and conventional correlation coefficients of 0.550 and 0.969, respectively. The combination of steric, electrostatic, hydrogen bond acceptor and hydrophobic fields in CoMSIA gave the best results with cross-validated and conventional correlation coefficients of 0.611 and 0.986, respectively. The predictive ability of CoMFA and CoMSIA were determined using a test set of 24 tricyclicpiperazinyl derivatives giving predictive correlation coefficients of 0.543 and 0.663, respectively, indicating good predictive power. Further the robustness of the model was verified by bootstrapping analysis. Based on the CoMFA and CoMSIA analysis we have identified some key features in the tricyclicpiperazinyl series that are responsible for farnesyltransferase inhibitory activity that may be used to design more potent tricyclicpiperazinyl derivatives and predict their activity prior to synthesis.
Puntambekar
D S
DS
Pharmacy Department, Faculty of Technology and Engineering, The MS University of Baroda, Vadodara-390001, Gujarat, India.
Giridhar
R
R
Yadav
M R
MR
D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D003198:Computer Simulation; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors*; D008958:Models, Molecular; D010879:Piperazines / Q000737:chemistry* / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D010879:Piperazines; D051231:Farnesyltranstransferase