Ligand design by targeting a binding site water

Area of Science:

• Biochemistry
• Computational Chemistry
• Pharmacology

Background:

• Solvent reorganization is key to protein-ligand binding.
• The specific role of binding site water networks in ligand affinity remains unclear.

Purpose of the Study:

• To investigate how modifying interactions with binding site water influences ligand affinity.
• To explore the impact of ordered water displacement on receptor binding.

Main Methods:

• Experimental evaluation of ligand series for the adenosine A2A receptor.
• Molecular dynamics simulations to analyze binding interactions and energetics.
• Thermodynamic profiling of substituent effects on binding affinity.

Main Results:

• A ligand analog unable to hydrogen bond with ordered water showed reduced affinity, accurately predicted by simulations.
• Designed compounds displacing ordered water yielded a novel adenosine A2A receptor agonist with nanomolar activity.
• Enthalpy-driven affinity gains were observed, influenced by water displacement to bulk solvent.

Conclusions:

• Altering interactions with binding site water networks is a viable strategy for modulating ligand affinity.
• Displacing water from binding sites can contribute significantly to binding enthalpy, a factor often overlooked in drug design.
• Findings offer insights into protein-ligand binding thermodynamics and rational drug discovery approaches.