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

Abstract

Human dihydroorotate dehydrogenase (hDHODH) is a class-2 dihydroorotate dehydrogenase. Because it is extensively used by proliferating cells, its inhibition in autoimmune and inflammatory diseases, cancers, and multiple sclerosis is of substantial clinical importance. In this study, we had two aims. The first was to develop an hDHODH pharma-similarity index approach (PhSIA) using integrated molecular dynamics calculations, pharmacophore hypothesis, and comparative molecular similarity index analysis (CoMSIA) contour information techniques. The approach, for the discovery and design of novel inhibitors, was based on 25 diverse known hDHODH inhibitors. Three statistical methods were used to verify the performance of hDHODH PhSIA. Fischer’s cross-validation test provided a 98% confidence level and the goodness of hit (GH) test score was 0.61. The q2, r2, and predictive r2 values were 0.55, 0.97, and 0.92, respectively, for a partial least squares validation method. In our approach, each diverse inhibitor structure could easily be aligned with contour information, and common substructures were unnecessary. For our second aim, we used the proposed approach to design 13 novel hDHODH inhibitors using a scaffold-hopping strategy. Chemical features of the approach were divided into two groups, and the Vitas-M Laboratory fragment was used to create de novo inhibitors. This approach provides a useful tool for the discovery and design of potential inhibitors of hDHODH, and does not require docking analysis; thus, our method can assist medicinal chemists in their efforts to identify novel inhibitors.

Identification of DHODH as a therapeutic target in small cell lung cancer

“…Furthermore, the responses of these models to brequinar treatment do not appear to correlate with sensitivity to currently used chemotherapy or a clinical history of chemotherapy exposure. This raises the prospect of using brequinar or other DHODH inhibitors (20,49,50) in human SCLC clinical trials, either as a single agent or in combination with standard of care.…”

Experimental approach, theoretical investigation and molecular docking of 2- chloro-5-fluoro phenol antibacterial compound

“…In current research, hDHODH inhibitors have been proved as an effective drug against rheumatoid arthritis, multiple sclerosis, inflammatory disorders and cancer therapy as studied by Ahmed. F. Abdel-Magnd [55,56,57]. The molecular docking is performed on 2C5FP as a ligand with the selected proteins using Auto dock Vina software.…”