X-ray Structure-Based Chemoinformatic Analysis Identifies Promiscuous Ligands Binding to Proteins from Different...

Area of Science:

• Computational chemistry
• Structural biology
• Pharmacology

Background:

• Compounds with multitarget activity are crucial for understanding promiscuous binding and polypharmacology in drug discovery.
• Exploring molecular interactions of such compounds aids in basic research and therapeutic development.

Purpose of the Study:

• To systematically identify compounds that bind to proteins across different classes.
• To compare the bioactive conformations and molecular properties of these multiclass ligands (MCLs).

Main Methods:

• Large-scale computational analysis integrating X-ray crystallography data, ligand binding modes, and compound activity.
• Evaluation of diverse molecular properties and binding characteristics.

Main Results:

• Identified 515 multitarget ligands, including 70 MCLs binding to proteins from distinct classes.
• MCLs were characterized as flexible, hydrophilic, and exhibiting a wide spectrum of binding modes.
• Binding shapes of MCLs showed both similarity and distinctness across different protein targets.

Conclusions:

• Combined structural and activity data revealed compounds active against proteins with diverse structures and functions.
• No canonical binding shapes were identified for MCLs; conformational versatility is key to their multitarget activity.
• Findings advance the understanding of promiscuous binding and inform the design of polypharmacological agents.