Postprocessing of docked protein-ligand complexes using implicit solvation models

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Fältnamn	Indikatorer	Metadata
000		04617naa a2200625 4500
001		oai:DiVA.org:umu-39985
003		SwePub
008		110214s2011 \| \|\|\|\|\|\|\|\|\|\|\|000 \|\|eng\|
024	7	a https://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-399852 URI
024	7	a https://doi.org/10.1021/ci100354x2 DOI
040		a (SwePub)umu
041		a engb eng
042		9 SwePub
072	7	a ref2 swepub-contenttype
072	7	a art2 swepub-publicationtype
100	1	a Lindström, Anton,d 1976-u Umeå universitet,Radiofysik4 aut0 (Swepub:umu)anli0018
245	1 0	a Postprocessing of docked protein-ligand complexes using implicit solvation models
264		c 2011-02-10
264	1	b American Chemical Society (ACS),c 2011
338		a print2 rdacarrier
520		a 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.
650	7	a NATURVETENSKAPx Kemi0 (SwePub)1042 hsv//swe
650	7	a NATURAL SCIENCESx Chemical Sciences0 (SwePub)1042 hsv//eng
650	7	a NATURVETENSKAPx Kemix Organisk kemi0 (SwePub)104052 hsv//swe
650	7	a NATURAL SCIENCESx Chemical Sciencesx Organic Chemistry0 (SwePub)104052 hsv//eng
650	7	a NATURVETENSKAPx Kemix Teoretisk kemi0 (SwePub)104072 hsv//swe
650	7	a NATURAL SCIENCESx Chemical Sciencesx Theoretical Chemistry0 (SwePub)104072 hsv//eng
653		a Solvation
653		a docking
653		a MMPBSA
653		a MMGBSA
653		a Post processing
653		a pose optimization
653		a Faxtor Xa
653		a MHC
653		a Chemistry
653		a Kemi
653		a Organic chemistry
653		a Organisk kemi
653		a Theoretical chemistry
653		a Teoretisk kemi
653		a organisk kemi
653		a Organic Chemistry
653		a computational linguistics
653		a datorlingvistik
700	1	a Edvinsson, Lottau Umeå universitet,Kemiska institutionen4 aut0 (Swepub:umu)loed0002
700	1	a Johansson, Andreasu Umeå universitet,Kemiska institutionen4 aut
700	1	a Andersson, C Davidu Umeå universitet,Kemiska institutionen4 aut0 (Swepub:umu)dadaon01
700	1	a Andersson, Ida Eu Umeå universitet,Kemiska institutionen4 aut0 (Swepub:umu)idaann02
700	1	a Raubacher, Florian4 aut
700	1	a Linusson, Annau Umeå universitet,Kemiska institutionen4 aut0 (Swepub:umu)analin99
710	2	a Umeå universitetb Radiofysik4 org
773	0	t Journal of chemical information and modelingd : American Chemical Society (ACS)g 51:2, s. 267-282q 51:2<267-282x 1549-960Xx 1549-9596
856	4 8	u https://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-39985
856	4 8	u https://doi.org/10.1021/ci100354x

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