Bioactivity of dihydropyrimidinone derivatives as inhibitors of cyclooxygenase-2 (COX-2): an in silico approach

Cyclooxygenase-2 (COX-2) is an enzyme involved in inflammation. The overexpression of COX-2 causes chronic inflammation, which can be prevented by COX-2 inhibitors. Generally, COX-2 inhibitors possess a carboxyl group and an aromatic ring in their molecular structure. These moieties are involved in the interaction with the active site of COX-2, thus playing a pivotal role in the inhibitory activity. Regarding the requisite molecular structure of COX-2 inhibitors, derivatives of dihydropyrimidinone (DHPM) are ideal candidates to be explored as COX-2 inhibitors, due to the ease of synthesis and their versatility to be transformed chemically. In this study, we prepared a novel small library consisting of 288 designed DHPM derivatives by varying the constituent components. The selection criteria of potential candidates for the COX-2 inhibitor of the data bank involve in silico studies via molecular docking investigations, prediction of ADMET and druglikeness, as well as molecular dynamics (MD) simulations. Molecular docking served as the initial step of selection, based on the comparison of grid score, docking pose, and interactions with those of lumiracoxib (LUR) as the original ligand of COX-2. The next criteria of selection were scores obtained from the ADMET and druglikeness by comparing the designed candidates with COX-2 inhibitors that were already marketed. Compound RDUE2 and SDT29 were the most potential candidates, which were further analyzed using the MD simulation. The results of the MD simulation indicated that RDUE2 and SDT29 interacted stably with amino acid residues on the active site of COX-2. The estimation of binding free energy indicated that SDT29 exhibited an inhibitory activity comparable to that of LUR, whereas RDUE2 showed a lower inhibitory activity than that of SDT29 and LUR.