Structure-based design and computational evaluation of new acrylamide derivatives as potent inhibitors of human dihydroorotate dehydrogenase for the treatment of rheumatoid arthritis

Human dihydroorotate dehydrogenase (DHODH) is a therapeutic target for the treatment of rheumatoid arthritis (RA). The development of new DHODH inhibitors could facilitate the discovery of a drug for RA therapy and contribute to sustainable health by promoting the design of safer and more efficient treatments. Using 3D-QSAR modeling techniques, we established a quantitative relationship between the DHODH inhibitory activity of 35 acrylamide derivatives (M1-M35) and their molecular fields. This model guided the design of 22 new acrylamide-based molecules (P1-P22) predicted to exhibit higher activity than M35, the most active in the initial database. The designed molecules were then docked into the DHODH active site, and the resulting complexes were evaluated using MM-GBSA free binding energy calculations. These analyses identified P4, P11, and P18 as the most DHODH inhibitors with docking scores and binding free energies superior to those of M35. The ADMET properties of the P4, P11, and P18 molecules were also predicted. The results show that they have good pharmacokinetic properties and are non-toxic. The molecular dynamics simulations of both free DHODH and its complexes with the best candidates confirmed the stability and validity of the obtained results. Finally, molecules P4, P11, and P18 show excellent capacity to inhibit the DHODH protein for the treatment of RA.