FEW: a workflow tool for free energy calculations of ligand binding

Journal of Computational Chemistry
Nadine Homeyer, Holger Gohlke

Abstract

In the later stages of drug design projects, accurately predicting relative binding affinities of chemically similar compounds to a biomolecular target is of utmost importance for making decisions based on the ranking of such compounds. So far, the extensive application of binding free energy approaches has been hampered by the complex and time-consuming setup of such calculations. We introduce the free energy workflow (FEW) tool that facilitates setup and execution of binding free energy calculations with the AMBER suite for multiple ligands. FEW allows performing free energy calculations according to the implicit solvent molecular mechanics (MM-PB(GB)SA), the linear interaction energy, and the thermodynamic integration approaches. We describe the tool's architecture and functionality and demonstrate in a show case study on Factor Xa inhibitors that the time needed for the preparation and analysis of free energy calculations is considerably reduced with FEW compared to a fully manual procedure.

References

Sep 28, 2013·Journal of Computer-aided Molecular Design·Shuai LiuDavid L Mobley
Apr 4, 2015·Expert Opinion on Drug Discovery·Samuel Genheden, Ulf Ryde
Nov 7, 2015·Journal of Chemical Information and Modeling·Hannes H LoefflerChristopher Woods
Jul 17, 2015·Journal of Chemical Information and Modeling·Williams E MirandaPedro A Valiente
Mar 10, 2015·European Journal of Medicinal Chemistry·Berin Karaman, Wolfgang Sippl
Dec 24, 2016·Journal of the American Chemical Society·Matteo AldeghiPhilip C Biggin
Nov 22, 2017·Journal of Cheminformatics·Luigi CapoferriDaan P Geerke
Dec 28, 2019·Journal of Computational Chemistry·Lucas WäschenbachHolger Gohlke
Sep 2, 2020·Journal of Computer-aided Molecular Design·Kai Liu, Hironori Kokubo
Apr 4, 2019·Journal of Cheminformatics·Willem JespersHugo Gutiérrez-de-Terán
Jul 7, 2020·Frontiers in Molecular Biosciences·Eko Aditya RifaiDaan P Geerke
Jan 29, 2014·Physical Chemistry Chemical Physics : PCCP·Julien Michel
Jun 6, 2014·Physical Chemistry Chemical Physics : PCCP·Francisco Adasme-CarreñoJans H Alzate-Morales

Citations

May 25, 1977·Journal of Molecular Biology·F C BernsteinM Tasumi
Mar 1, 1994·Protein Engineering·Johan ÅqvistJ E Samuelsson
Jul 10, 1999·Bioorganic & Medicinal Chemistry·M L LambWilliam L Jorgensen
Oct 24, 2002·Journal of Computational Chemistry·Araz JakalianChristopher I Bayly
Nov 25, 2003·Advances in Protein Chemistry·Bjørn O BrandsdalJohan Åqvist
Dec 4, 2003·Journal of Computational Chemistry·Holger Gohlke, David A Case
Mar 20, 2004·Science·William L Jorgensen
Apr 30, 2004·Journal of Computational Chemistry·Junmei WangDavid A Case
Oct 4, 2005·Journal of Computational Chemistry·David A CaseRobert J Woods
Jan 5, 2007·Annual Review of Biophysics and Biomolecular Structure·Michael K Gilson, Huan-Xiang Zhou
Oct 9, 2007·The Journal of Physical Chemistry. B·Chunhu TanRay Luo
Dec 28, 2007·Journal of Medicinal Chemistry·Yu-Kai LeeMark R Player
Jan 30, 2008·Journal of the American Chemical Society·Ileana StoicaPeter V Coveney
Mar 21, 2008·Journal of Computational Chemistry·Sunhwan JoWonpil Im
Jan 9, 2009·Current Drug Targets·Hermes Luís Neubauer de AmorimPaulo Augusto Netz
May 29, 2010·Journal of Computer-aided Molecular Design·Julien Michel, Jonathan W Essex
Sep 15, 2010·Journal of Computational Chemistry·Pedro A ValientePedro G Pascutti
Nov 6, 2010·Journal of Computer-aided Molecular Design·Markus A Lill, Matthew L Danielson
Aug 23, 2011·Biotechnology Advances·Marco Daniele Parenti, Giulio Rastelli
Sep 29, 2011·Journal of Computational Chemistry·Thomas SteinbrecherDavid A Case
Sep 17, 2010·Molecular Informatics·Julien MichelJonathan W Essex
Feb 1, 2012·Molecular Informatics·Nadine Homeyer, Holger Gohlke

Related Concepts

Thermodynamics
Molecular Dynamics
Ligand Binding
Plasma Protein Binding Capacity
Computer Programs and Programming
Chemicals
Indirect Thrombin Inhibitors
Factor Xa Inhibitors [MoA]
Ligands
Direct Factor Xa Inhibitors

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