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dc.contributor.authorGranadino, Jose Manuel
dc.contributor.authorMey, Antonia S. J. S.
dc.contributor.authorPérez González, Juan Jesús
dc.contributor.authorBosisio, Stefano
dc.contributor.authorRubio Martínez, Jaime
dc.contributor.authorMichel, Julien
dc.contributor.otherUniversitat Politècnica de Catalunya. Departament d'Enginyeria Química
dc.identifier.citationGranadino, J. [et al.]. Effect of set up protocols on the accuracy of alchemical free energy calculation over a set of ACK1 inhibitors. "PloS one", 1 Març 2019, vol. 14, núm. 3, p. e0213217.
dc.description.abstractHit-to-lead virtual screening frequently relies on a cascade of computational methods that starts with rapid calculations applied to a large number of compounds and ends with more expensive computations restricted to a subset of compounds that passed initial filters. This work focuses on set up protocols for alchemical free energy (AFE) scoring in the context of a Docking–MM/PBSA–AFE cascade. A dataset of 15 congeneric inhibitors of the ACK1 protein was used to evaluate the performance of AFE set up protocols that varied in the steps taken to prepare input files (using previously docked and best scored poses, manual selection of poses, manual placement of binding site water molecules). The main finding is that use of knowledge derived from X-ray structures to model binding modes, together with the manual placement of a bridging water molecule, improves the R2 from 0.45 ± 0.06 to 0.76 ± 0.02 and decreases the mean unsigned error from 2.11 ± 0.08 to 1.24 ± 0.04 kcal mol-1. By contrast a brute force automated protocol that increased the sampling time ten-fold lead to little improvements in accuracy. Besides, it is shown that for the present dataset hysteresis can be used to flag poses that need further attention even without prior knowledge of experimental binding affinities
dc.publisherPublic Library of Science (PLOS)
dc.rightsAttribution-NonCommercial-NoDerivs 3.0 Spain
dc.subjectÀrees temàtiques de la UPC::Enginyeria química
dc.titleEffect of set up protocols on the accuracy of alchemical free energy calculation over a set of ACK1 inhibitors
dc.contributor.groupUniversitat Politècnica de Catalunya. GBMI - Grup de Biotecnologia Molecular i Industrial
dc.description.peerreviewedPeer Reviewed
dc.rights.accessOpen Access
dc.description.versionPostprint (published version)
upcommons.citation.authorGranadino, J.; Mey, A.; Perez, J.; Bosisio, S.; Rubio, J.; Michel, J.
upcommons.citation.publicationNamePloS one

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