Accurate conformation-dependent molecular electrostatic potentials for high-throughput in silico drug discovery

Area of Science:

• Computational chemistry
• Molecular modeling
• Drug discovery

Background:

• Atom-centered partial charges are crucial for molecular modeling, offering a computationally efficient alternative to quantum mechanics for electrostatic calculations.
• Despite advances in ab initio methods, partial charge approximations remain valuable in computational chemistry.

Purpose of the Study:

• To develop new parameters for Electronegativity Equalization Method (EEM) and its variant SFKEEM.
• To enable rapid and accurate determination of partial charges for flexible molecules.
• To enhance the modeling of electrostatic potentials in pharmaceutical chemistry.

Main Methods:

• Developed and validated new parameters for EEM and SFKEEM.
• Utilized B3LYP/cc-pVTZ as a reference for electrostatic potential calculations.
• Tested the methods on a set of FDA-approved drug molecules.

Main Results:

• The new parameters accurately model the electrostatic potential of flexible molecules.
• Charges derived using these parameters achieve an average accuracy of 13 +/- 4 kJ mol(-1) compared to B3LYP/cc-pVTZ.
• Electronegativity equalization methods with these parameters demonstrate accuracy comparable to AM1-BCC.

Conclusions:

• The developed EEM and SFKEEM parameters offer a computationally inexpensive yet accurate approach for partial charge calculation.
• These methods provide a competitive alternative to existing non-quantum mechanical methods for molecular electrostatics.
• The parameters are integrated into the BALLOON software for broader accessibility.