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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