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Understanding the antitumor activity of novel tricyclicpiperazinyl derivatives as farnesyltransferase inhibitors using CoMFA and CoMSIA.
Eur J Med Chem. 2006 Nov; 41(11):1279-92.EJ

Abstract

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.

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Authors+Show Affiliations

Puntambekar DS
Pharmacy Department, Faculty of Technology and Engineering, The MS University of Baroda, Vadodara-390001, Gujarat, India.
Giridhar R
No affiliation info available
Yadav MR
No affiliation info available

MeSH

Antineoplastic AgentsComputer SimulationEnzyme InhibitorsFarnesyltranstransferaseModels, MolecularPiperazinesQuantitative Structure-Activity Relationship

Pub Type(s)

Comparative Study
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16919851

Citation

Puntambekar, D S., et al. "Understanding the Antitumor Activity of Novel Tricyclicpiperazinyl Derivatives as Farnesyltransferase Inhibitors Using CoMFA and CoMSIA." European Journal of Medicinal Chemistry, vol. 41, no. 11, 2006, pp. 1279-92.
Puntambekar DS, Giridhar R, Yadav MR. Understanding the antitumor activity of novel tricyclicpiperazinyl derivatives as farnesyltransferase inhibitors using CoMFA and CoMSIA. Eur J Med Chem. 2006;41(11):1279-92.
Puntambekar, D. S., Giridhar, R., & Yadav, M. R. (2006). Understanding the antitumor activity of novel tricyclicpiperazinyl derivatives as farnesyltransferase inhibitors using CoMFA and CoMSIA. European Journal of Medicinal Chemistry, 41(11), 1279-92.
Puntambekar DS, Giridhar R, Yadav MR. Understanding the Antitumor Activity of Novel Tricyclicpiperazinyl Derivatives as Farnesyltransferase Inhibitors Using CoMFA and CoMSIA. Eur J Med Chem. 2006;41(11):1279-92. PubMed PMID: 16919851.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Understanding the antitumor activity of novel tricyclicpiperazinyl derivatives as farnesyltransferase inhibitors using CoMFA and CoMSIA. AU - Puntambekar,D S, AU - Giridhar,R, AU - Yadav,M R, Y1 - 2006/08/21/ PY - 2006/07/02/revised PY - 2006/07/03/accepted PY - 2006/8/22/pubmed PY - 2007/1/31/medline PY - 2006/8/22/entrez SP - 1279 EP - 92 JF - European journal of medicinal chemistry JO - Eur J Med Chem VL - 41 IS - 11 N2 - 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. SN - 0223-5234 UR - https://www.unboundmedicine.com/medline/citation/16919851/Understanding_the_antitumor_activity_of_novel_tricyclicpiperazinyl_derivatives_as_farnesyltransferase_inhibitors_using_CoMFA_and_CoMSIA_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0223-5234(06)00230-3 DB - PRIME DP - Unbound Medicine ER -