Molecular Modelling and Virtual Screening to Identify New Piperazine Derivatives as Potent Human 5-HT1A Antagonists and Reuptake Inhibitors.

Abstract

Serotonin/5-HT antagonist and reuptake inhibitors (SARIs) ameliorate depression by increasing the terminal 5-HT through the activation of somatodendritic 5-HT1A autoreceptors. In addition to their therapeutic application as standalone antidepressants, they are co-administered with selective serotonin reuptake inhibitors (SSRI) to improve unpleasant side effects associated with SSRI-treated depression. However, only a few of the atypical antidepressants are available and not without some serious aftereffects. This study aims at the identification of novel promising SARIs using computational chemistry and high throughput screening. Pharmacophore features were modelled using LigandScout 4.3 and validated through the area under curve (AUC), enrichment factor (EF) and Guner-Henry (GH) scores. Molecular docking was employed for virtual screening against modelled human 5HT1A homology receptor, molecular dynamics simulations and ADMET predictions. The adopted pharmacophore possesses AUC, EF and GH scores of 0.7, 30.9 and 0.6 respectively, thus validated and used for molecular database screening. The modelled 5-HT1A homology receptor, validated using RCSB structure validation protocols, was employed for molecular docking and dynamics simulations. From the IBScreen database, the ligands, STOCK6S-36853, STOCK7S-36094, STOCK3S-94557, STOCK7S-28769 and STOCK5S-36248 interacted more strongly against the 5-HT1A receptor with docking scores of -8.735, -8.677, -8.140, -7.911 and -7.710 kcal/mol, and binding free energy of -29.72, -38.87, -29.85, -7.65 and -34.71 kcal/mol respectively, compared to fluoxetine and trazodone (positive controls) while albendazole and metformin (negative controls) scored least. They demonstrated good stability, satisfy the BDDCS RO5 and thus, are identified as potent SARIs. The study represents a cost-effective, faster and environmentally friendly approach to the discovery of promising SARI antidepressants for further translational study.