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3D-QSAR CoMFA/CoMSIA studies on Urokinase plasminogen activator (uPA) inhibitors: a strategic design in novel anticancer agents.
Bioorg Med Chem. 2004 May 15; 12(10):2797-805.BM

Abstract

Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) was performed on a series of indole/benzoimidazole-5-carboxamidines as urokinase plasminogen activator (uPA) inhibitors. The ligand molecular superimposition on template structure was performed by atom/shape-based RMS fit, multifit, and RMSD fit methods. The removal of two outliers from the initial training set of 30 molecules improved the predictivity of the models. The statistically significant model was established from 28 molecules, which were validated by evaluation of test set of nine compounds. The atom-based RMS alignment yielded best predictive CoMFA model (r2(cv) = 0.611, r2(cnv) = 0.778, F value = 43.825, r2(bs) = 0.842, r2(pred) = 0.616 with two components) while the CoMSIA model yielded (r2(cv) = 0.499, r2(cnv) = 0.976, F value=96.36, r2(bs) = 0.993, r2(pred) = 0.694 with eight components). The contour maps obtained from 3D-QSAR studies were appraised for the activity trends of the molecules analyzed. The results indicate that the steric, electrostatic, and hydrogen bond donor/acceptor substituents play significant role in uPA activity and selectivity of these compounds. The data generated from the present study can be used as putative pharmacophore in the design of novel, potent, and selective urokinase plasminogen activator inhibitors as cancer therapeutics.

Authors+Show Affiliations

Bhongade BA
Department of Medicinal Chemistry, College of Pharmacy, J. N. Medical College, Belgaum 590010, Karnataka, India.
Gadad AK
No affiliation info available

MeSH

AmidinesAntineoplastic AgentsBenzimidazolesDrug DesignIndolesMolecular ConformationPlasminogen InactivatorsQuantitative Structure-Activity RelationshipUrokinase-Type Plasminogen Activator

Pub Type(s)

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

Language

eng

PubMed ID

15110861

Citation

Bhongade, B A., and A K. Gadad. "3D-QSAR CoMFA/CoMSIA Studies On Urokinase Plasminogen Activator (uPA) Inhibitors: a Strategic Design in Novel Anticancer Agents." Bioorganic & Medicinal Chemistry, vol. 12, no. 10, 2004, pp. 2797-805.
Bhongade BA, Gadad AK. 3D-QSAR CoMFA/CoMSIA studies on Urokinase plasminogen activator (uPA) inhibitors: a strategic design in novel anticancer agents. Bioorg Med Chem. 2004;12(10):2797-805.
Bhongade, B. A., & Gadad, A. K. (2004). 3D-QSAR CoMFA/CoMSIA studies on Urokinase plasminogen activator (uPA) inhibitors: a strategic design in novel anticancer agents. Bioorganic & Medicinal Chemistry, 12(10), 2797-805.
Bhongade BA, Gadad AK. 3D-QSAR CoMFA/CoMSIA Studies On Urokinase Plasminogen Activator (uPA) Inhibitors: a Strategic Design in Novel Anticancer Agents. Bioorg Med Chem. 2004 May 15;12(10):2797-805. PubMed PMID: 15110861.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 3D-QSAR CoMFA/CoMSIA studies on Urokinase plasminogen activator (uPA) inhibitors: a strategic design in novel anticancer agents. AU - Bhongade,B A, AU - Gadad,A K, PY - 2003/12/22/received PY - 2004/02/16/revised PY - 2004/02/17/accepted PY - 2004/4/28/pubmed PY - 2004/12/16/medline PY - 2004/4/28/entrez SP - 2797 EP - 805 JF - Bioorganic & medicinal chemistry JO - Bioorg Med Chem VL - 12 IS - 10 N2 - Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) was performed on a series of indole/benzoimidazole-5-carboxamidines as urokinase plasminogen activator (uPA) inhibitors. The ligand molecular superimposition on template structure was performed by atom/shape-based RMS fit, multifit, and RMSD fit methods. The removal of two outliers from the initial training set of 30 molecules improved the predictivity of the models. The statistically significant model was established from 28 molecules, which were validated by evaluation of test set of nine compounds. The atom-based RMS alignment yielded best predictive CoMFA model (r2(cv) = 0.611, r2(cnv) = 0.778, F value = 43.825, r2(bs) = 0.842, r2(pred) = 0.616 with two components) while the CoMSIA model yielded (r2(cv) = 0.499, r2(cnv) = 0.976, F value=96.36, r2(bs) = 0.993, r2(pred) = 0.694 with eight components). The contour maps obtained from 3D-QSAR studies were appraised for the activity trends of the molecules analyzed. The results indicate that the steric, electrostatic, and hydrogen bond donor/acceptor substituents play significant role in uPA activity and selectivity of these compounds. The data generated from the present study can be used as putative pharmacophore in the design of novel, potent, and selective urokinase plasminogen activator inhibitors as cancer therapeutics. SN - 0968-0896 UR - https://www.unboundmedicine.com/medline/citation/15110861/3D_QSAR_CoMFA/CoMSIA_studies_on_Urokinase_plasminogen_activator__uPA__inhibitors:_a_strategic_design_in_novel_anticancer_agents_ DB - PRIME DP - Unbound Medicine ER -