Carbazole derivatives as promising competitive and allosteric inhibitors of human serotonin transporter: computational pharmacology

Abstract

The human serotonin transporters (hSERTs) are neurotransmitter sodium symporters of the aminergic G protein-coupled receptors, regulating the synaptic serotonin and neuropharmacological processes related to neuropsychiatric disorders, notably, depression. Selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine and (S)-citalopram are competitive inhibitors of hSERTs and are commonly the first-line medications for major depressive disorder (MDD). However, treatment-resistance and unpleasant aftereffects constitute their clinical drawbacks. Interestingly, vilazodone emerged with polypharmacological (competitive and allosteric) inhibitions on hSERTs, amenable to improved efficacy. However, its application usually warrants adjuvant/combination therapy, another subject of critical adverse events. Thus, the discovery of alternatives with polypharmacological potentials (one-drug-multiple-target) and improved safety remains essential. In this study, carbazole analogues from chemical libraries were explored using docking and molecular dynamics (MD) simulation. Selectively, two IBScreen ligands, STOCK3S-30866 and STOCK1N-37454 predictively bound to the active pockets and expanded boundaries (extracellular vestibules) of the hSERTs more potently than vilazodone and (S)-citalopram. For instance, the two ligands showed docking scores of −9.52 and −9.59 kcal/mol and MM-GBSA scores of −92.96 and −65.66 kcal/mol respectively compared to vilazodone’s respective scores of −7.828 and −59.27 against the central active site of the hSERT (PDB 7LWD). Similarly, the two ligands also docked to the allosteric pocket (PDB 5I73) with scores of −8.15 and −8.40 kcal/mol and MM-GBSA of −96.14 and −68.46 kcal/mol whereas (S)-citalopram has −6.90 and −69.39 kcal/mol respectively. The ligands also conferred conformational stability on the receptors during 100 ns MD simulations and displayed interesting ADMET profiles, representing promising hSERT modulators for MDD upon experimental validation.

Communicated by Ramaswamy H. Sarma

Keywords:

• Major depressive disorder
• serotonergic pathways
• human serotonin transporter
• molecular dynamics
• carbazole alkaloids
• computational pharmacology

Author contributions

The manuscript was written with the contributions of all authors. All authors have approved the final version of the manuscript. Conceptualization, literature survey, data collection and writing by YOA, data collection and writing by AI, HP, CFC, NAZ and SYN, visualization, research supervision and manuscript revision by MNM.

Disclosure statement

The authors declare no conflict of interest.

Additional information

Funding

This work was financially supported by the Tertiary Education Fund Nigeria, Fundamental Research Grant Scheme, Ministry of Higher Education of Malaysia (grant no. 203.CDADAH.6711955). YOA is thankful to the Universiti Sains Malaysia for GA Scheme (grant no. 308.AIPS.415401).