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The MM/PBSA and MM/GBSA methods to estimate ligand-binding affinities

Genheden, Samuel and Ryde, Ulf LU (2015) In Expert Opinion on Drug Discovery 10(5). p.449-461
Abstract
Introduction: The molecular mechanics energies combined with the Poisson-Boltzmann or generalized Born and surface area continuum solvation (MM/PBSA and MM/GBSA) methods are popular approaches to estimate the free energy of the binding of small ligands to biological macromolecules. They are typically based on molecular dynamics simulations of the receptor-ligand complex and are therefore intermediate in both accuracy and computational effort between empirical scoring and strict alchemical perturbation methods. They have been applied to a large number of systems with varying success. Areas covered: The authors review the use of MM/PBSA and MM/GBSA methods to calculate ligand-binding affinities, with an emphasis on calibration, testing and... (More)
Introduction: The molecular mechanics energies combined with the Poisson-Boltzmann or generalized Born and surface area continuum solvation (MM/PBSA and MM/GBSA) methods are popular approaches to estimate the free energy of the binding of small ligands to biological macromolecules. They are typically based on molecular dynamics simulations of the receptor-ligand complex and are therefore intermediate in both accuracy and computational effort between empirical scoring and strict alchemical perturbation methods. They have been applied to a large number of systems with varying success. Areas covered: The authors review the use of MM/PBSA and MM/GBSA methods to calculate ligand-binding affinities, with an emphasis on calibration, testing and validation, as well as attempts to improve the methods, rather than on specific applications. Expert opinion: MM/PBSA and MM/GBSA are attractive approaches owing to their modular nature and that they do not require calculations on a training set. They have been used successfully to reproduce and rationalize experimental findings and to improve the results of virtual screening and docking. However, they contain several crude and questionable approximations, for example, the lack of conformational entropy and information about the number and free energy of water molecules in the binding site. Moreover, there are many variants of the method and their performance varies strongly with the tested system. Likewise, most attempts to ameliorate the methods with more accurate approaches, for example, quantum-mechanical calculations, polarizable force fields or improved solvation have deteriorated the results. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
drug design, electrostatics, entropy, free energy perturbation, linear, interaction energy, non-polar solvation, solvation
in
Expert Opinion on Drug Discovery
volume
10
issue
5
pages
449 - 461
publisher
Informa Healthcare
external identifiers
  • wos:000353208600002
  • scopus:84928313330
ISSN
1746-0441
DOI
10.1517/17460441.2015.1032936
language
English
LU publication?
yes
id
15915054-8ac4-4e84-a92c-5f161a52fc7d (old id 5386089)
date added to LUP
2015-05-18 14:35:19
date last changed
2017-11-12 03:15:10
@article{15915054-8ac4-4e84-a92c-5f161a52fc7d,
  abstract     = {Introduction: The molecular mechanics energies combined with the Poisson-Boltzmann or generalized Born and surface area continuum solvation (MM/PBSA and MM/GBSA) methods are popular approaches to estimate the free energy of the binding of small ligands to biological macromolecules. They are typically based on molecular dynamics simulations of the receptor-ligand complex and are therefore intermediate in both accuracy and computational effort between empirical scoring and strict alchemical perturbation methods. They have been applied to a large number of systems with varying success. Areas covered: The authors review the use of MM/PBSA and MM/GBSA methods to calculate ligand-binding affinities, with an emphasis on calibration, testing and validation, as well as attempts to improve the methods, rather than on specific applications. Expert opinion: MM/PBSA and MM/GBSA are attractive approaches owing to their modular nature and that they do not require calculations on a training set. They have been used successfully to reproduce and rationalize experimental findings and to improve the results of virtual screening and docking. However, they contain several crude and questionable approximations, for example, the lack of conformational entropy and information about the number and free energy of water molecules in the binding site. Moreover, there are many variants of the method and their performance varies strongly with the tested system. Likewise, most attempts to ameliorate the methods with more accurate approaches, for example, quantum-mechanical calculations, polarizable force fields or improved solvation have deteriorated the results.},
  author       = {Genheden, Samuel and Ryde, Ulf},
  issn         = {1746-0441},
  keyword      = {drug design,electrostatics,entropy,free energy perturbation,linear,interaction energy,non-polar solvation,solvation},
  language     = {eng},
  number       = {5},
  pages        = {449--461},
  publisher    = {Informa Healthcare},
  series       = {Expert Opinion on Drug Discovery},
  title        = {The MM/PBSA and MM/GBSA methods to estimate ligand-binding affinities},
  url          = {http://dx.doi.org/10.1517/17460441.2015.1032936},
  volume       = {10},
  year         = {2015},
}