Target-ligand binding affinity from single point enthalpy calculation and elemental composition.

Area of Science:

• Computational chemistry
• Biophysics
• Drug discovery

Background:

• Accurate target-ligand binding thermodynamics are crucial for drug design.
• Existing theoretical methods often overlook electronic effects and explicit water molecules.
• There is a need for efficient computational tools to predict binding thermodynamics.

Purpose of the Study:

• To introduce QMH-L, a fast calculator for estimating target-ligand binding free energy.
• To incorporate electronic effects and explicit water molecules into binding energy predictions.
• To enable rapid, automated scoring of drug candidates and ligand engineering.

Main Methods:

• QMH-L uses a pre-optimized target-ligand complex structure.
• It combines semi-empirical quantum mechanics for binding enthalpy with a ligand elemental composition descriptor.
• Explicit water molecules at the interface are predicted and included.

Main Results:

• QMH-L estimates binding free energy with a root mean square error of 0.94 kcal mol⁻¹.
• Calculated binding enthalpy values show good agreement with experimental isothermal titration calorimetry data.
• The method was validated using diverse protein targets and large peptide ligands.

Conclusions:

• QMH-L provides a computationally inexpensive and rapid method for predicting binding thermodynamics.
• The calculator effectively handles electronic effects and explicit water molecules.
• QMH-L is suitable for virtual screening, ligand design, and understanding complex interactions.