标题：Profiling the antidepressant properties of phenyl piperidine derivatives as inhibitors of serotonin transporter (SERT) via cheminformatics modeling, molecular docking and ADMET predictions.
摘要：AbstractThe inhibition of serotonin transporter (SERT) has been considered to be a good target for the treatment of mood disorders (depression). The present study employed cheminformatics modeling, molecular docking analysis and ADMET predictions approaches on some Phenyl piperidine derivatives reported as inhibitors of serotonin transporter to determine the structural and physicochemical parameters of the compounds responsible for the inhibition, to elucidate the binding interactions between the receptor and the ligands and to predict the ADMET properties of the compounds as antidepressant agents. A validated cheminformatics model was developed using Density Functional Theory (DFT/B3LYP/6-31G*) by utilizing the Genetic Function Algorithm for variable selections. The obtained statistical parameters of the model (R2Train = 0.8572, R2Test = 0.678 and cR2p= 0.763) showed that the model was well predicted, robust, reliable and very stable. Similarly, five molecular descriptors (AATS8v, GATS1e, SpMAD_Dzs, SP-7 and RDF135v) were found to be significantly correlated to the inhibitory activity of the compounds in the developed model. Likewise, the molecular docking analysis elucidates the important interactions between the amino acid residues at the active site of the receptor between the ligands. Four ligands (1,2,5 and 6) were selected which portend higher binding affinity (-10.1, -10.2, -10.4 and -10.5 kcal/mol) with the lower RMSD values compared to the standard drug (Brexpiprazole) with a smaller binding affinity (-8.1 kcal/ mol) and elevated RMSD value. All the selected compounds revealed to be orally bioavailable and pharmacologically active because none of the compounds violate Lipinski's rule of five. The ADMET predictions show that all the selected compounds including Brexpiprazole were non-inhibitors of CYP3A4 and CYP2D6 cytochrome P450 enzymes with attributes of good blood-brain barrier (BBB) penetration, excellent gastrointestinal (GI) absorption and are unlikely to exhibit cardiovascular toxicity (hERG toxicity). As a consequence, the methodology employed in this study and the obtained results could serve as a reliable framework to uncover novel Phenyl piperidine analogues and for the rational design of potential inhibitors of the serotonin transporter (SERT) as antidepressant agents.
