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Effect of set up protocols on the accuracy of alchemical free energy calculation over a set of ACK1 inhibitors

View ORCID ProfileJosé M. Granadino-Roldán, Antonia S. J. S. Mey, Juan J. Pérez González, Stefano Bosisio, Jaime Rubio-Martinez, Julien Michel
doi: https://doi.org/10.1101/333120
José M. Granadino-Roldán
aDepartamento de Química Física, Facultad de Ciencias Experimentales, Universidad de Jaén, Campus “Las Lagunillas” s/n, 23071, Jaén, Spain
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  • ORCID record for José M. Granadino-Roldán
Antonia S. J. S. Mey
bEaStCHEM School of Chemistry, Joseph Black Building, The King’s Buildings, Edinburgh, EH9 3FJ, UK
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Juan J. Pérez González
cDepartment of Chemical Engineering, Universitat Politecnica de Catalunya, ETSEIB. Av. Diagonal, 647, 08028 Barcelona, Spain
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Stefano Bosisio
bEaStCHEM School of Chemistry, Joseph Black Building, The King’s Buildings, Edinburgh, EH9 3FJ, UK
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Jaime Rubio-Martinez
dDepartament de Química Física, Universitat de Barcelona (UB) and the Institut de Recerca en Quimica Teorica i Computacional (IQTCUB), Martí i Franqués 1, 08028 Barcelona, Spain
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Julien Michel
bEaStCHEM School of Chemistry, Joseph Black Building, The King’s Buildings, Edinburgh, EH9 3FJ, UK
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ABSTRACT

Hit-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.

Footnotes

  • ↵* José M. Granadino-Roldán. E-mail jmroldan{at}ujaen.es

  • ↵* Julien Michel. E-mail julien.michel{at}ed.ac.uk

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted February 14, 2019.
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Effect of set up protocols on the accuracy of alchemical free energy calculation over a set of ACK1 inhibitors
José M. Granadino-Roldán, Antonia S. J. S. Mey, Juan J. Pérez González, Stefano Bosisio, Jaime Rubio-Martinez, Julien Michel
bioRxiv 333120; doi: https://doi.org/10.1101/333120
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Effect of set up protocols on the accuracy of alchemical free energy calculation over a set of ACK1 inhibitors
José M. Granadino-Roldán, Antonia S. J. S. Mey, Juan J. Pérez González, Stefano Bosisio, Jaime Rubio-Martinez, Julien Michel
bioRxiv 333120; doi: https://doi.org/10.1101/333120

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