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

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.

Type 2 diabetic mellitus related osteoporosis: focusing on ferroptosis

“…(5) Dihydroorotate dehydrogenase (DHODH) is a flavin-dependent enzyme located in the mitochondrial inner membrane, catalyzing the fourth step of pyrimidine nucleotide synthesis [ 60 ]. DHODH suppresses mitochondrial iron apoptosis by regulating the production of the coenzyme QH2 (CoQH2) in the inner mitochondrial membrane [ 61 ].…”

Dihydroorotate dehydrogenase regulates ferroptosis in neurons after spinal cord injury via the P53‐ALOX15 signaling pathway

“…It catalyzes the fourth step in the synthesis of pyrimidine nucleotides (oxidation of DHO to OA and reduction of ubiquinone to CoQH 2 ). 7 A recent study by Mao et al 8 showed that DHODH has been demonstrated to prevent mitochondrial ferroptosis by regulating CoQH2 synthesis in the inner mitochondrial membrane. DHODH is a key mechanism that inhibits the anticancer activity of ferroptosis.…”

Development of a Human Dihydroorotate Dehydrogenase (hDHODH) Pharma-Similarity Index Approach with Scaffold-Hopping Strategy for the Design of Novel Potential Inhibitors

“…[33]), and CoMFA/CoMSIA (Vyas et al . [34]). For example, Vyas et al [34] used a series of aryl carboxylic acid amide derivatives for QSAR or CoMFA/CoMSIA calculation.…”

“…[34]). For example, Vyas et al [34] used a series of aryl carboxylic acid amide derivatives for QSAR or CoMFA/CoMSIA calculation. These previous approaches have a common factor that is need a common sub-structure for inhibitor alignment calculation.…”