Identification of novel serotonin transporter compounds by virtual screening

Area of Science:

• Neuroscience
• Pharmacology
• Computational Chemistry

Background:

• The serotonin transporter (SERT) is crucial for regulating serotonergic neurotransmission.
• SERT is a key target for antidepressant and psychostimulant medications.

Purpose of the Study:

• To discover novel small molecules that bind to SERT.
• To identify compounds with potential therapeutic applications for neurological and psychiatric disorders.

Main Methods:

• Screening of ~3.24 million compounds from five commercial databases.
• Utilized 2D fingerprint and 3D pharmacophore-based virtual screening.
• Employed flexible docking against an outward-open SERT homology model.

Main Results:

• Identified 74 active compounds across 16 structural classes.
• 46 compounds exhibited K(i) values ≤1000 nM.
• Discovered multiple novel SERT binders structurally distinct from known inhibitors.

Conclusions:

• The multistep virtual screening and hit-to-lead approach successfully identified potent SERT inhibitors.
• The novel chemical entities provide a foundation for developing new SERT-targeted therapeutics.
• This study expands the chemical space for SERT modulator discovery.