Flexible scaffold-based cheminformatics approach for polypharmacological drug design

Area of Science:

• Medicinal Chemistry
• Neuroscience
• Computational Chemistry

Background:

• Treatments for complex central nervous system (CNS) disorders necessitate drugs with polypharmacology and multifunctionality.
• Designing multi-target drugs remains a significant challenge in medicinal chemistry.

Purpose of the Study:

• To present a novel flexible scaffold-based cheminformatics approach (FSCA) for the rational design of polypharmacological drugs.
• To demonstrate the application of FSCA using a novel compound targeting 5-HT2A and 5-HT1A receptors.

Main Methods:

• FSCA involves fitting a flexible scaffold to different receptors using distinct binding poses.
• Analysis of aminergic receptor structures identified key motifs: 'agonist filter' and 'conformation shaper'.
• The compound IHCH-7179 was designed using FSCA, adopting different binding poses at 5-HT2A and 5-HT1A receptors.

Main Results:

• IHCH-7179 acted as an antagonist at 5-HT2A receptors and an agonist at 5-HT1A receptors.
• IHCH-7179 demonstrated efficacy in alleviating cognitive deficits and psychoactive symptoms in mouse models.
• The identified motifs predict ligand binding pose and activity at aminergic receptors.

Conclusions:

• FSCA provides a rational strategy for designing polypharmacological drugs.
• The identified motifs are crucial for predicting ligand behavior at aminergic receptors.
• FSCA can be extended to design polypharmacological ligands for other receptor targets.