Please use this identifier to cite or link to this item:
Title: Effect of set up protocols on the accuracy of alchemical free energy calculation over a set of ACK1 inhibitors
Author: Granadino Roldán, José M.
Mey, Antonia S. J. S.
Pérez González, Juan J.
Bosisio, Stefano
Rubio Martínez, Jaime
Michel, Julien
Keywords: Termodinàmica
Dinàmica molecular
Molecular dynamics
Issue Date: 12-Mar-2019
Publisher: Public Library of Science (PLoS)
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.
Note: Reproducció del document publicat a:
It is part of: PLoS One, 2019, vol. 14, num. 3, p. e0213217
Related resource:
ISSN: 1932-6203
Appears in Collections:Articles publicats en revistes (Ciència dels Materials i Química Física)
Articles publicats en revistes (Institut de Química Teòrica i Computacional (IQTCUB))

Files in This Item:
File Description SizeFormat 
694569.pdf2.44 MBAdobe PDFView/Open

This item is licensed under a Creative Commons License Creative Commons