EXPLORING THE BINDING MODES OF PIPERAZINE COMPOUNDS ON MAO-A FOR A STEP TOWARDS DEPRESSION THERAPY

Abstract

Sadness, often referred to as “depression,” is a normal emotion. The World Health Organization (WHO) claims that depression is a prevalent psychological condition that affects 264 million people worldwide, involving complex interactions between social and psychological behaviors. Piperazine, a heterocyclic scaffold, has been extensively used in various research studies due to its remarkable pharmacological effects in pharmaceutical chemistry. It has been modified to discover a new reversible neuroactive compound, along with pyrazoline. Early investigations have demonstrated significant inhibition of MAO-A by both compounds. The docking of molecules was performed by employing Autodock Vina programme, an in silico approach. Using the docking software AutoDockTools 1.5.6, the molecular docking studies on MAO-A enzyme targeting depression [Protein Data Bank (PDB) ID: 2BXR] was conducted. Compound C17, demonstrated significant interactions with specific residues, including Gly25, Arg51, Ser24, Thr435, Lys305, Gly66, Tyr407, Cys406, Gly67, Gly443, Ile23, Thr52, Gly22 and Ala448. This finding suggests that compound 17 could potentially serve as a promising and innovative candidate for the treatment of depression. This study focuses on designing a hybrid molecule combining piperazine and pyrazoline as MAO-A inhibitors. The results of the study indicate that C17 and C20 exhibit the greatest affinity, having interaction values of -10.9 kcal mol-1 and -10.8 kcal mol-1, respectively. All the chemicals demonstrated similar behavior within the binding pocket of MAO-A. In this study, the in silico tool Swiss ADME were used to predict the drug-likeness of all designed compounds. The analysis indicated that all the compounds, except one, comply with Lipinski’s rule of five, which defines the druglike compounds. Further, synthesis and biological evaluations need to be conducted in the future.