Structural Insight into 2-Aryl-4-Quinoline Carboxylic Acid-Based Dihydroorotate Dehydrogenase (DHODH) and its Potential Anti-SARS-CoV-2 Activity Through Pharmacophore Modeling, Multidimensional QSAR, ADME, and Docking Studies

Dihydroorotate dehydrogenase (DHODH) is a rate-limiting enzyme in the biosynthesis of pyrimidone that catalyzes the oxidation of dihydro-orotate to orotate. Uridine-monophosphate is biosynthesized using orotate. DHODH inhibitors have demonstrated antiviral activity against Cytomegalovirus, Ebola, Influenza, Epstein-Barr virus, and Picornavirus. DHODH inhibitors' anti-SARS-CoV-2 activity is also being investigated. DHODH inhibitors (leflunomide and its metabolite teriflunomide) have been demonstrated to have anti-SARS-CoV-2 activity. In relation with the importance of this enzyme in drug designing, in present analysis, we have developed 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 analogues reported as DHODH inhibitors. The correlation coefficient R2 values of training set of the PLS and all five KPLS models for the respective fingerprints were obtained as 0.7091, 0.8336 (linear), 0.7586 (radial), 0.8606 (dendritic), 0.6832 (desc) and 0.7670 (molprint2D) respectively (R2 ≈ 0.9 but > 0.6), while the external validation coefficient Q2 values (Q2 > 0.6) of the test set are 0.7009, 0.7503 (linear), 0.7737 (radial), 0.8250 (dendritic), 0.6756 (desc) and 0.7533 (molprint2D) with lower values of uncertainties.