Discovery of Thiadiazoles as Human Dihydroorotate Dehydrogenase (hDHODH) Inhibitors by Combined Structure‐Based Modelling Methods

Abstract

This study involves the design of novel thiadiazole derivatives as hDHODH inhibitors using various structure‐based approaches such as pharmacophore modelling, high‐throughput virtual screening (HTVS), prediction of ADMET parameters, docking and molecular dynamics (MD) studies. We used the validated co‐crystal structure of hDHODH to create the six‐feature pharmacophore model ADHRRR, which was validated by the Güner‐Henry scoring (GH score=0.81) approach, enrichment calculations (enrichment factor=51), area under the curve (0.93), receiving operating characteristic (ROC) curve (0.89), and ROC′s Boltzmann‐enhanced discrimination, known as BEDROC (α=8) (0.859), (α=20) (0.828), (α=160) (0.912). Pharmacophore model as a 3D search query was used for the screening of zinc database followed by docking investigations and energy calculation (Prime/MMGBSA). For the design of novel compounds, we selected the thiadiazole moiety as the central scaffold and various functional groups based on pharmacophoric characters and binding interactions. In docking study, designed compounds showed favourable interactions with Gln47 and Arg136 at the active site of the hDHODH enzyme, and optimal drug likeness properties for ADMET prediction study. Stability of enzyme‐ligand complex was validated by MD simulation study with RMSD, RMSF and RoG calculations. These findings suggested that novel thiadiazoles are potential candidates as hDHODH inhibitors and anticancer agents.