In Silico Evaluation of 3,4-Dihydropyrimidin-2(1H)-Ones as Potential Antioxidant Agents: Molecular Docking and ADME/T Studies

Abstract

Reactive oxygen species and endogenous antioxidants are essential for normal cellular metabolism; however, an imbalance between them causes oxidative stress, which significantly contributes to the onset and progression of various diseases, including neurodegenerative, cancer, and cardiovascular disorders. Thus, designing new antioxidant scaffolds is an important research priority. Among the many heterocycles, 3,4-dihydropyrimidin-2(1H)- one (DHPM) derivatives are particularly appealing because of their structural diversity and simple synthesis route through the Biginelli reaction. This study aimed to identify potent antioxidant DHPM derivatives using a structure-based computational approach. The target protein (PDB ID: 4IQK) was prepared and optimised for docking studies. Standard antioxidant drugs were retrieved from the PubChem database. The generated compounds were subjected to molecular modeling to evaluate their binding affinities with the target protein. In addition, the pharmacokinetic and ADME/T properties of the compounds were assessed using pkCSM. Among the thirty DHPM derivatives evaluated, six derivatives had strong binding affinities, with values between -7.9 and -8.0 kcal/mol. Compound DHPM 22 was the most powerful lead among them. It exhibited a better binding affinity of -8.0 kcal/mol because it formed hydrogen bonds, π-π stacking, and hydrophobic interactions with the protein's active site. Furthermore, ADME/T analysis confirmed the favorable drug-likeness and pharmacokinetic properties of the selected compounds. The docking and ADME/T studies of the 3,4-dihydropyrimidin-2(1H)-one derivatives showed favorable antioxidant activity against the Keap protein with PDB ID: 4IQK. Amongst the designed compounds, compound DHPM 22 showed the highest binding affinity (- 8.0 kcal/mol), which was comparable to the standard 4-bromoflavone (-8.5 kcal/mol). This enhanced binding affinity can be attributed to the formation of conventional hydrogen bonds with Gly367A, Val465A, and Gly464A, hydrophobic interactions with Val418A, Ile416A, Ala366A, Leu557A, Leu365A, Val604A, and Val606A, as well as a π-alkyl interaction with Ile559A, collectively contributing to the stabilization of the ligand within the active site. Compounds DHPM 3 and DHPM 29 also showed favorable binding scores of -7.9 and -7.8 kcal/mol, respectively. The structure-activity relationship suggests that the electron-withdrawing groups like fluoro and bromo enhanced binding affinity, whereas bulky polar substituents reduced the antioxidant activity. Overall, the present study demonstrates that DHPM derivatives, specifically DHPM 22, may represent a promising lead for the development of new antioxidant derivatives. Further experimental studies are recommended to confirm their biological activities and therapeutic potential.