When Does Chemical Elaboration Induce a Ligand To Change Its Binding Mode?

Area of Science:

• Medicinal Chemistry
• Structural Biology
• Computational Chemistry

Background:

• Drug discovery often assumes ligands maintain their binding pose as they are optimized.
• Understanding ligand-receptor interactions is crucial for developing effective therapeutics.

Purpose of the Study:

• To investigate the frequency and drivers of binding mode changes during ligand elaboration.
• To evaluate the utility of structure-based modeling in predicting these changes.

Main Methods:

• Compilation of a large dataset of related ligand pairs bound to the same protein.
• Analysis of structural data to identify shifts in ligand binding modes.
• Correlation of binding mode changes with ligand physiochemical properties and computational modeling predictions.

Main Results:

• 14% (41 of 297) of ligand pairs exhibited altered binding modes upon structural elaboration.
• Specific physiochemical properties, characteristic of fragments, were associated with binding mode shifts.
• Structure-based modeling was more effective than physiochemical properties in identifying substitutions that alter binding modes.
• Observed changes were attributed to steric clashes or the emergence of new favorable interactions in alternative poses.

Conclusions:

• Ligand binding modes are not always conserved during hit-to-lead optimization.
• Structure-based modeling is a valuable tool for predicting and guiding optimization strategies that involve binding mode alterations.
• Scaffolds capable of adopting multiple binding poses offer opportunities for divergent drug optimization pathways.