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
Current Computer-Aided Drug Design
Title:CoMFA and CoMSIA Studies on Aryl Carboxylic Acid Amide Derivatives as Dihydroorotate Dehydrogenase (DHODH) Inhibitors
Volume: 8 Issue: 4
Author(s): Vivek K. Vyas and Manjunath Ghate
Affiliation:
Keywords: 3D QSAR, CoMFA, CoMSIA, hDHODH inhibitors, aryl carboxylic acid amide derivatives
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.
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K. Vyas Vivek and Ghate Manjunath, CoMFA and CoMSIA Studies on Aryl Carboxylic Acid Amide Derivatives as Dihydroorotate Dehydrogenase (DHODH) Inhibitors, Current Computer-Aided Drug Design 2012; 8 (4) . https://dx.doi.org/10.2174/157340912803519598
DOI https://dx.doi.org/10.2174/157340912803519598 |
Print ISSN 1573-4099 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-6697 |
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