Iterative Focused Screening with Biological Fingerprints Identifies Selective Asc-1 Inhibitors Distinct from...

Area of Science:

• Neuroscience
• Pharmacology
• Drug Discovery

Background:

• N-methyl-d-aspartate receptors (NMDARs) are crucial for cognitive functions; their hypofunction is implicated in schizophrenia and Alzheimer's disease.
• Enhancing NMDAR function by increasing synaptic co-agonists like d-serine is a therapeutic strategy.
• Alanine-serine-cysteine transporter-1 (Asc-1) is the primary transporter of d-serine and is strategically located in brain regions vital for cognition.

Purpose of the Study:

• To identify novel inhibitors of the alanine-serine-cysteine transporter-1 (Asc-1).
• To discover selective Asc-1 inhibitors for potential therapeutic development targeting cognitive deficits.

Main Methods:

• Employed two screening approaches: a high-throughput screen (HTS) and an iterative focused screen (IFS) using heterologous cells expressing human Asc-1.
• Utilized radiolabeled amino acid uptake assays (³⁵S l-cysteine and ³H d-serine) to measure transporter activity.
• Implemented counter screens to eliminate nonspecific inhibitors and incorporated computational models for hit selection in an expansion set.

Main Results:

• Identified novel chemical matter that selectively inhibits Asc-1.
• The iterative focused screen, combined with data-driven selection, yielded hits not found in the initial high-throughput screen.
• Demonstrated the effectiveness of counter screens and integrated data modeling in discovering specific transporter inhibitors.

Conclusions:

• Novel Asc-1 inhibitors were successfully identified through integrated screening strategies.
• These inhibitors represent promising candidates for developing treatments to address NMDAR hypofunction and associated cognitive impairments.
• The study highlights the value of targeted screening and data integration in drug discovery for neurological disorders.