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

The atom-centered partial charges-approximation is commonly used in current molecular modeling tools as a computationally inexpensive alternative to quantum mechanics for modeling electrostatics. Even today, the use of partial charges remains useful despite significant advances in improving the effi...

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Bibliographic Details
Published in:Journal of computational chemistry 2010-06, Vol.31 (8), p.1722-1732
Main Authors: Puranen, J. Santeri, Vainio, Mikko J, Johnson, Mark S
Format: Article
Language:English
Subjects:
Accuracy
Analytical chemistry
Atoms & subatomic particles
Calibration
Computer Simulation
conformation dependent
Drug Discovery
electronegativity equalization
Electrostatics
High-Throughput Screening Assays
Models, Molecular
Molecular Conformation
molecular electrostatic potential
Molecular structure
Parameter estimation
partial charges
Pharmaceutical Preparations - chemistry
polarizable
R&D
Reproducibility of Results
Research & development
Software
Static Electricity
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Summary:The atom-centered partial charges-approximation is commonly used in current molecular modeling tools as a computationally inexpensive alternative to quantum mechanics for modeling electrostatics. Even today, the use of partial charges remains useful despite significant advances in improving the efficiency of ab initio methods. Here, we report on new parameters for the EEM and SFKEEM electronegativity equalization-based methods for rapidly determining partial charges that will accurately model the electrostatic potential of flexible molecules. The developed parameters cover most pharmaceutically relevant chemistries, and charges obtained using these parameters reproduce the B3LYP/cc-pVTZ reference electrostatic potential of a set of FDA-approved drug molecules at best to an average accuracy of 13 ± 4 kJ mol⁻¹; thus, equipped with these parameters electronegativity equalization-based methods rival the current best non-quantum mechanical methods, such as AM1-BCC, in accuracy, yet incur a lower computational cost. Software implementations of EEM and SFKEEM, including the developed parameters, are included in the conformer-generation tool BALLOON, available free of charge at http://web.abo.fi/fak/mnf/bkf/research/johnson/software.php.
ISSN:0192-8651
1096-987X
DOI:10.1002/jcc.21460