Current Computer-Aided Drug Design

Subhash C. Basak
Departments of Chemistry, Biochemistry & Molecular Biology University of Minnesota Duluth
Duluth, MN 55811
USA

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CoMFA and CoMSIA Studies on Aryl Carboxylic Acid Amide Derivatives as Dihydroorotate Dehydrogenase (DHODH) Inhibitors

Author(s): Vivek K. Vyas, Manjunath Ghate.

Abstract:

DHODH is a flavoenzyme that catalyzes the oxidation of dihydroorotate (DHO) to orotate (ORO) as part of the fourth and rate limiting step of the de novo pyrimidine biosynthetic pathway. Inhibitors of DHODHs have proven efficacy for the treatment of cancer, malaria and immunological disorders. 3D QSAR studies on some aryl carboxylic acid amide derivatives as hDHODH 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 alignment strategy was used for these compounds by means of Distill function defined in SYBYL X 1.2. The best CoMFA and CoMSIA models obtained for the training set were statistically significant with cross-validated coefficients (q2) of 0.636 and 0.604 and conventional coefficients (r2) of 0.993 and 0.950, respectively. Both the models were validated by an external test set of five compounds giving satisfactory prediction (r2 pred) of 0.563 and 0.523 for CoMFA and CoMSIA models, respectively. Further the robustness of the model was verified by bootstrapping analysis. Generated CoMFA and CoMSIA models provide useful information for the design of novel inhibitors with good hDHODH inhibitory.

Keywords: 3D QSAR, CoMFA, CoMSIA, hDHODH inhibitors, aryl carboxylic acid amide derivatives

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Article Details

VOLUME: 8
ISSUE: 4
Year: 2012
Page: [271 - 282]
Pages: 12
DOI: 10.2174/157340912803519598
Price: $58