Molecular Docking and In-S ilico ADME Prediction of Substituted ( E )-4-Styryl-7,8-dihydroquinazolin-5(6 H )-ones and 5-(( E )-Styryl)pyrimidine[4,5-d]pyrimidine-2,4(1 H ,3 H )-diones as Potential SERT Inhibitors and Antidepressants

A set of 66 compounds from three classes having either of the two nuclei, (E)-4-styryl-7,8-dihydroquinazolin-5(6H)-one (1-22a and 1-22b) and 5-((E)-styryl)pyrimido[4,5-d]pyrimidine-2,4(1H,3H)-dione (1-22c) were docked with Serotonin reuptake transporter (SERT) using escitalopram as the reference compound for comparison. Five of the compounds (18b, 19a, 15c, 19c and 6a) had binding energy lower than/equal to that of escitalopram (-8.8 kcal/mol) and were eliminated from the study. The remaining 61 compounds were assessed for druglikeness using Lipinski’s rule of five which led to the elimination of one more compound (19b). From among the remaining 60 compounds, 31 having binding energy equal to/greater than -10 kcal/mol were submitted for ADME properties prediction on an online program (preADMET) and the analysis of the results, taking into consideration the compounds blood brain barrier penetration and predicted P-glycoprotein inhibition as the major criteria for elimination, 11 compounds were selected for synthesis and further study as antidepressant agents. None of the 5-((E)-styryl)pyrimido[4,5-d]pyrimidine-2,4(1H,3H)-dione made it to the final eleven compounds due to high polarity that limits their BBB penetration. From among the 11 selected for synthesis are 3 compounds also that have very good hepatic metabolism (CYP450 enzymes interactions) pharmacokinetic profiles, predicted. The compounds selected for synthesis preferentially bind to the allosteric site of the SERT.