Estimates of ligand-binding affinities supported by quantum mechanical methods

Interdisciplinary Sciences, Computational Life Sciences
Pär SöderhjelmUlf Ryde

Abstract

In this paper, we review our efforts to use quantum mechanical (QM) methods to improve free-energy estimates of the binding of drug candidates to their receptor proteins. First, we have tested the influence of various implicit solvation models on predictions of the ligand-binding affinity. The accuracy of implicit solvation models strongly depend on the parameterisation, but also on the magnitude of the solvation energy (i.e. their accuracy should be discussed in relative terms). However, if only relative solvation energies within a series of similar drug molecules with the same net charge are considered, nearly all methods tested give a comparable accuracy of 2-5 kJ/mol. Second, we have studied the conformational dependence of QM charges and their influence on ligand-binding affinities. The conformational dependence is significant, but it is to a large extent cancelled by solvation energies. Third, we have estimated the effect and range of electrostatic interactions beyond a point-charge model. The results show that multipoles up to octupoles and anisotropic polarisabilities have a significant influence on energies for residues up to 10-15 A from the ligand and that different sets of point-charge models may give strongly varyi...Continue Reading

References

Jan 1, 1990·Annual Review of Biophysics and Biophysical Chemistry·K A Sharp, B Honig
Jan 1, 1989·Annual Review of Biophysics and Biophysical Chemistry·D L Beveridge, F M DiCapua
Mar 1, 1994·Protein Engineering·J AqvistJ E Samuelsson
May 7, 1998·Journal of Computer-aided Molecular Design·T HanssonJ Aqvist
Apr 12, 2001·Current Opinion in Structural Biology·T A Halgren, W Damm
Mar 23, 2002·Journal of Computational Chemistry·Emma SigfridssonBruce L Bush
Oct 24, 2002·Journal of Computational Chemistry·Pengyu Ren, Jay W Ponder
Dec 4, 2003·Journal of Computational Chemistry·Holger Gohlke, David A Case
Jan 30, 2004·Journal of the American Chemical Society·Kaushik Raha, Kenneth M Merz
Jul 23, 2004·The Journal of Chemical Physics·Da W ZhangJohn Z H Zhang
Aug 31, 2004·The Journal of Chemical Physics·Laura GagliardiGunnar Karlström
Jun 10, 2005·Journal of Medicinal Chemistry·Bernd KuhnMartin Stahl
Aug 12, 2005·Chemical Reviews·Jacopo TomasiRoberto Cammi
Aug 13, 2005·The Journal of Chemical Physics·G Andrés CisnerosThomas A Darden
Jul 6, 2006·Journal of Biological Inorganic Chemistry : JBIC : a Publication of the Society of Biological Inorganic Chemistry·Frank Neese
Jul 11, 2006·The Journal of Chemical Physics·Pär SöderhjelmUlf Ryde
Oct 18, 2006·Accounts of Chemical Research·Per E M Siegbahn, Tomasz Borowski
Jan 5, 2007·Annual Review of Biophysics and Biomolecular Structure·Michael K Gilson, Huan-Xiang Zhou
Feb 3, 2007·Dalton Transactions : an International Journal of Inorganic Chemistry·Ulf Ryde
Aug 21, 2007·Journal of the American Chemical Society·Lisa M Miller JenkinsEttore Appella
Sep 11, 2007·Drug Discovery Today·Kaushik RahaKenneth M Merz
Oct 9, 2007·The Journal of Physical Chemistry. B·Chunhu TanRay Luo
Jan 15, 2008·The Journal of Chemical Physics·Pär SöderhjelmGunnar Karlström
Jan 25, 2008·Journal of Medicinal Chemistry·Anthony NichollsVijay S Pande
Sep 6, 2008·Journal of Computational Chemistry·Pär Söderhjelm, Ulf Ryde
Sep 11, 2008·Journal of Computer-aided Molecular Design·Jacob Kongsted, Ulf Ryde
Jul 2, 2009·Journal of Computational Chemistry·Giulio RastelliMiriam Sgobba
Jul 15, 2009·Journal of Computational Chemistry·Samuel Genheden, Ulf Ryde

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Citations

Jun 28, 2011·Journal of Computer-aided Molecular Design·Antonella CiancettaUlf Ryde
Apr 5, 2014·Journal of Computer-aided Molecular Design·Paulius MikulskisUlf Ryde
Apr 15, 2016·Chemical Reviews·Ulf Ryde, Pär Söderhjelm
Sep 8, 2016·Journal of Computer-aided Molecular Design·Octav CaldararuUlf Ryde
May 28, 2020·Physical Chemistry Chemical Physics : PCCP·Jinfeng Liu, Xiao He
May 10, 2012·Journal of Computational Chemistry·Jens Antony, Stefan Grimme
Mar 1, 2014·Biophysics Reviews·Isabella A GuedesLaurent E Dardenne
Jun 8, 2010·The Journal of Physical Chemistry. B·Samuel GenhedenUlf Ryde
Apr 23, 2021·Physical Chemistry Chemical Physics : PCCP·Lennart GundelachChris-Kriton Skylaris
Oct 10, 2014·Journal of Chemical Information and Modeling·Prasad ChaskarUte F Röhrig

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