Postprocessing of docked protein-ligand complexes using implicit solvation models

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Lindström, Anton,1976-Umeå universitet,Radiofysik (author)

Postprocessing of docked protein-ligand complexes using implicit solvation models

Article/chapterEnglish2011

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2011-02-10
American Chemical Society (ACS),2011
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LIBRIS-ID:oai:DiVA.org:umu-39985
https://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-39985URI
https://doi.org/10.1021/ci100354xDOI

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Language:English
Summary in:English

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Subject category:ref swepub-contenttype
Subject category:art swepub-publicationtype

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Molecular docking plays an important role in drug discovery as a tool for the structure-based design of small organic ligands for macromolecules. Possible applications of docking are identification of the bioactive conformation of a protein−ligand complex and the ranking of different ligands with respect to their strength of binding to a particular target. We have investigated the effect of implicit water on the postprocessing of binding poses generated by molecular docking using MM-PB/GB-SA (molecular mechanics Poisson−Boltzmann and generalized Born surface area) methodology. The investigation was divided into three parts: geometry optimization, pose selection, and estimation of the relative binding energies of docked protein−ligand complexes. Appropriate geometry optimization afforded more accurate binding poses for 20% of the complexes investigated. The time required for this step was greatly reduced by minimizing the energy of the binding site using GB solvation models rather than minimizing the entire complex using the PB model. By optimizing the geometries of docking poses using the GBHCT+SA model then calculating their free energies of binding using the PB implicit solvent model, binding poses similar to those observed in crystal structures were obtained. Rescoring of these poses according to their calculated binding energies resulted in improved correlations with experimental binding data. These correlations could be further improved by applying the postprocessing to several of the most highly ranked poses rather than focusing exclusively on the top-scored pose. The postprocessing protocol was successfully applied to the analysis of a set of Factor Xa inhibitors and a set of glycopeptide ligands for the class II major histocompatibility complex (MHC) Aq protein. These results indicate that the protocol for the postprocessing of docked protein−ligand complexes developed in this paper may be generally useful for structure-based design in drug discovery.

Subject headings and genre

NATURVETENSKAP Kemi hsv//swe
NATURAL SCIENCES Chemical Sciences hsv//eng
NATURVETENSKAP Kemi Organisk kemi hsv//swe
NATURAL SCIENCES Chemical Sciences Organic Chemistry hsv//eng
NATURVETENSKAP Kemi Teoretisk kemi hsv//swe
NATURAL SCIENCES Chemical Sciences Theoretical Chemistry hsv//eng
Solvation
docking
MMPBSA
MMGBSA
Post processing
pose optimization
Faxtor Xa
MHC
Chemistry
Kemi
Organic chemistry
Organisk kemi
Theoretical chemistry
Teoretisk kemi
organisk kemi
Organic Chemistry
computational linguistics
datorlingvistik

Added entries (persons, corporate bodies, meetings, titles ...)

Edvinsson, LottaUmeå universitet,Kemiska institutionen(Swepub:umu)loed0002 (author)
Johansson, AndreasUmeå universitet,Kemiska institutionen (author)
Andersson, C DavidUmeå universitet,Kemiska institutionen(Swepub:umu)dadaon01 (author)
Andersson, Ida EUmeå universitet,Kemiska institutionen(Swepub:umu)idaann02 (author)
Raubacher, Florian (author)
Linusson, AnnaUmeå universitet,Kemiska institutionen(Swepub:umu)analin99 (author)
Umeå universitetRadiofysik (creator_code:org_t)

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In:Journal of chemical information and modeling: American Chemical Society (ACS)51:2, s. 267-2821549-960X1549-9596

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NATURAL SCIENCES: NATURAL SCIENCES; and Chemical Science ...

NATURAL SCIENCES: NATURAL SCIENCES; and Chemical Science ...; and Organic Chemistr ...

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