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Ligand-Binding Affinity Estimates Supported by Quantum-Mechanical Methods

Ryde, Ulf LU and Söderhjelm, Pär LU (2016) In Chemical Reviews 116(9). p.5520-5566
Abstract

One of the largest challenges of computational chemistry is calculation of accurate free energies for the binding of a small molecule to a biological macromolecule, which has immense implications in drug development. It is well-known that standard molecular-mechanics force fields used in most such calculations have a limited accuracy. Therefore, there has been a great interest in improving the estimates using quantum-mechanical (QM) methods. We review here approaches involving explicit QM energies to calculate binding affinities, with an emphasis on the methods, rather than on specific applications. Many different QM methods have been employed, ranging from semiempirical QM calculations, via density-functional theory, to strict... (More)

One of the largest challenges of computational chemistry is calculation of accurate free energies for the binding of a small molecule to a biological macromolecule, which has immense implications in drug development. It is well-known that standard molecular-mechanics force fields used in most such calculations have a limited accuracy. Therefore, there has been a great interest in improving the estimates using quantum-mechanical (QM) methods. We review here approaches involving explicit QM energies to calculate binding affinities, with an emphasis on the methods, rather than on specific applications. Many different QM methods have been employed, ranging from semiempirical QM calculations, via density-functional theory, to strict coupled-cluster calculations. Dispersion and other empirical corrections are mandatory for the approximate methods, as well as large basis sets for the stricter methods. QM has been used for the ligand, for a few crucial groups around the ligand, for all the closest atoms (200-1000 atoms), or for the full receptor-ligand complex, but it is likely that with a proper embedding it might be enough to include all groups within ∼6 Å of the ligand. Approaches involving minimized structures, simulations of the end states of the binding reaction, or full free-energy simulations have been tested.

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Chemical Reviews
volume
116
issue
9
pages
47 pages
publisher
The American Chemical Society
external identifiers
  • Scopus:84969593568
ISSN
0009-2665
DOI
10.1021/acs.chemrev.5b00630
language
English
LU publication?
yes
id
d10ee0e5-f397-449e-ab11-e06e32cd9a5a
date added to LUP
2016-07-08 13:11:25
date last changed
2017-02-05 20:47:31
@article{d10ee0e5-f397-449e-ab11-e06e32cd9a5a,
  abstract     = {<p>One of the largest challenges of computational chemistry is calculation of accurate free energies for the binding of a small molecule to a biological macromolecule, which has immense implications in drug development. It is well-known that standard molecular-mechanics force fields used in most such calculations have a limited accuracy. Therefore, there has been a great interest in improving the estimates using quantum-mechanical (QM) methods. We review here approaches involving explicit QM energies to calculate binding affinities, with an emphasis on the methods, rather than on specific applications. Many different QM methods have been employed, ranging from semiempirical QM calculations, via density-functional theory, to strict coupled-cluster calculations. Dispersion and other empirical corrections are mandatory for the approximate methods, as well as large basis sets for the stricter methods. QM has been used for the ligand, for a few crucial groups around the ligand, for all the closest atoms (200-1000 atoms), or for the full receptor-ligand complex, but it is likely that with a proper embedding it might be enough to include all groups within ∼6 Å of the ligand. Approaches involving minimized structures, simulations of the end states of the binding reaction, or full free-energy simulations have been tested.</p>},
  author       = {Ryde, Ulf and Söderhjelm, Pär},
  issn         = {0009-2665},
  language     = {eng},
  month        = {05},
  number       = {9},
  pages        = {5520--5566},
  publisher    = {The American Chemical Society},
  series       = {Chemical Reviews},
  title        = {Ligand-Binding Affinity Estimates Supported by Quantum-Mechanical Methods},
  url          = {http://dx.doi.org/10.1021/acs.chemrev.5b00630},
  volume       = {116},
  year         = {2016},
}