Targeting histidine side chains in molecular design through nitrogen-halogen bonds

Area of Science:

• Biochemistry
• Computational Chemistry
• Medicinal Chemistry

Background:

• Halogen bonds are directional noncovalent interactions.
• They can target electron donors within protein binding sites.

Purpose of the Study:

• To explore halogen···nitrogen contacts involving histidine side chains using quantum chemical calculations.
• To derive simple rules for predicting preferred interaction areas in binding sites.

Main Methods:

• Quantum chemical calculations (MP2 level of theory).
• Utilized SCS-MP2 and CCSD(T)/CBS for reference calculations.
• Analyzed energy profiles in suboptimal geometries.

Main Results:

• Characterized energetics of nitrogen-halogen bonds with histidine.
• Developed predictive rules for interaction site preference.
• Identified significant potential for increasing binding affinities and tuning subtype selectivities.

Conclusions:

• Nitrogen-halogen bonds are valuable but underexploited in drug discovery.
• These interactions can be leveraged for scaffold decoration and design.
• They offer a promising avenue for enhancing drug efficacy and selectivity.