ABSTRACT
Dihydroorotate dehydrogenase (DHODH) is a rate-limiting enzyme in the biosynthesis of pyrimidine, which catalyzes the oxidation of dihydroorotate to orotate. Uridine monophosphate is biosynthesized by orotate. DHODH inhibitors have been shown to have antiviral activity against cytomegalovirus, Ebola, influenza, Epstein-Barr virus, and picornavirus. The anti-SARS-CoV-2 activity of DHODH inhibitors has also been investigated. DHODH inhibitors, including leflunomide and its metabolite teriflunomide, have been found to have anti-SARSCoV-2 activity. In relation to the importance of this enzyme (i.e., DHODH) in drug design, the present study aimed to develop statistically robust and interpretable 2D and 3D-quantitative structure-activity relationship (QSAR) models based on a dataset of 92 molecules of biologically active 2-aryl-4-quinoline carboxylic acid analogs, reported as DHODH inhibitors. The correlation coefficient (R2) values of the training set of the partial least squares (PLS) and all five Kernel-based PLS models for the respective fingerprints were found to be 0.7091, 0.8336 (linear), 0.7586 (radial), 0.8606 (dendritic), 0.6832 (desc), and 0.7670 (Molprint 2D), respectively (R2 ≈ 0.9). However, the external validation coefficient (Q2) values of the test set were found to be 0.7009, 0.7503 (linear), 0.7737 (radial), 0.8250 (dendritic), 0.6756 (desc), and 0.7533 (Molprint 2D), respectively (Q2 > 0.6). The developed 4-point pharmacophore model (ARRR_1), with one hydrogen bond acceptor and three aromatic rings, was found to be crucial in preserving the activity of 2-aryl-4-quinoline carboxylic acid analogs as DHODH inhibitors. Furthermore, the molecular docking of DHODH inhibitors against SARS-CoV-2 target proteins revealed the significant role of DHODH inhibitors. © 2023, Physical Chemistry Research. All Rights Reserved.