Identifying Promiscuous Compounds with Activity against Different Target Classes.

Area of Science:

• Medicinal Chemistry
• Drug Discovery
• Computational Biology

Background:

• Polypharmacology, utilizing compounds with multitarget activity, is crucial for modern drug discovery.
• Understanding how promiscuous compounds interact with diverse targets aids in developing novel therapeutics.

Purpose of the Study:

• To systematically identify compounds exhibiting activity against drug targets from different protein classes.
• To curate a collection of highly promiscuous compounds for pharmaceutical applications and molecular binding studies.

Main Methods:

• Analysis of public biological screening data, with careful exclusion of compounds prone to experimental artifacts.
• Identification and characterization of extensively assayed compounds, categorizing them by activity profiles (inactive, single-target, or promiscuous).

Main Results:

• Over 1000 multiclass ligands were identified, each active against 10 or more targets from different classes.
• Exemplary compounds were structurally validated through X-ray crystallography in complexes with distinct targets.
• A comprehensive dataset of promiscuous compounds was compiled, filtering out false positives.

Conclusions:

• The identified collection of multiclass ligands presents significant opportunities for drug discovery and understanding structure-activity relationships.
• Making these highly promiscuous compounds publicly available will accelerate research in polypharmacology and molecular interactions.