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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Published in | Journal of computational chemistry Vol. 31; no. 8; pp. 1722 - 1732 |
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Main Authors | , , |
Format | Journal Article |
Language | English |
Published |
Hoboken
Wiley Subscription Services, Inc., A Wiley Company
01.06.2010
Wiley Subscription Services, Inc |
Subjects | |
Online Access | Get full text |
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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. |
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Bibliography: | http://dx.doi.org/10.1002/jcc.21460 Stiftelsens för Åbo Akademi forskningsinstitut and the Center of Excellence in Cell Stress Sigrid Jusélius Foundation istex:79CAE262CF91FE5DD4D17D806CBE0CBFD205B6FD ArticleID:JCC21460 Magnus Ehrnrooth Foundation The Academy of Finland Medicinska understödsföreningen Liv och Hälsa K. Albin Johansson Foundation ark:/67375/WNG-TV1MWSQH-K Svenska kulturfonden ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 0192-8651 1096-987X |
DOI: | 10.1002/jcc.21460 |