Coupled atomic charge selectivity for optimal ligand-charge distributions at protein binding sites

Area of Science:

• Computational chemistry
• Molecular modeling
• Drug design

Background:

• Charge optimization is crucial for understanding and improving molecular binding electrostatics.
• Existing methods for charge selectivity analysis do not account for coupled charge changes.

Purpose of the Study:

• To develop and apply a novel method for characterizing charge selectivity in a concerted manner.
• To analyze the coupled charge selectivity of celecoxib binding to COX2 and CAII.

Main Methods:

• Developed a novel approach for calculating concerted charge selectivity.
• Applied the method to celecoxib, a ligand binding to cyclooxygenase 2 (COX2) and carbonic anhydrase II (CAII).
• Compared uncoupled and coupled charge selectivity profiles.

Main Results:

• The novel method accounts for coupled changes in atomic charges, unlike previous approaches.
• Celecoxib exhibits distinct charge selectivity profiles when binding to COX2 versus CAII.
• Coupled charge selectivity calculations yield significantly different results compared to uncoupled methods.

Conclusions:

• Concerted charge selectivity analysis provides a more accurate representation of ligand-protein interactions.
• The findings offer insights into the cross-reactivity of celecoxib and can guide future molecular design.
• This approach enhances the understanding of binding electrostatics and molecular recognition.