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QligFEP: an automated workflow for small molecule free energy calculations in Q
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.ORCID iD: 0000-0002-4951-9220
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.ORCID iD: 0000-0003-2091-0610
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics. Uppsala University, Science for Life Laboratory, SciLifeLab.ORCID iD: 0000-0003-0459-3491
2019 (English)In: Journal of Cheminformatics, ISSN 1758-2946, E-ISSN 1758-2946, Vol. 11, article id 26Article in journal (Refereed) Published
Abstract [en]

The process of ligand binding to a biological target can be represented as the equilibrium between the relevant solvated and bound states of the ligand. This which is the basis of structure-based, rigorous methods such as the estimation of relative binding affinities by free energy perturbation (FEP). Despite the growing capacity of computing power and the development of more accurate force fields, a high throughput application of FEP is currently hampered due to the need, in the current schemes, of an expert user definition of the alchemical transformations between molecules in the series explored. Here, we present QligFEP, a solution to this problem using an automated workflow for FEP calculations based on a dual topology approach. In this scheme, the starting poses of each of the two ligands, for which the relative affinity is to be calculated, are explicitly present in the MD simulations associated with the (dual topology) FEP transformation, making the perturbation pathway between the two ligands univocal. We show that this generalized method can be applied to accurately estimate solvation free energies for amino acid sidechain mimics, as well as the binding affinity shifts due to the chemical changes typical of lead optimization processes. This is illustrated in a number of protein systems extracted from other FEP studies in the literature: inhibitors of CDK2 kinase and a series of A(2A) adenosine G protein-coupled receptor antagonists, where the results obtained with QligFEP are in excellent agreement with experimental data. In addition, our protocol allows for scaffold hopping perturbations to identify the binding affinities between different core scaffolds, which we illustrate with a series of Chk1 kinase inhibitors. QligFEP is implemented in the open-source MD package Q, and works with the most common family of force fields: OPLS, CHARMM and AMBER.

Place, publisher, year, edition, pages
BMC , 2019. Vol. 11, article id 26
Keywords [en]
Free energy perturbation (FEP), Molecular dynamics (MD), Ligand binding, Application programming interface (API), Dual topology
National Category
Biochemistry and Molecular Biology
Identifiers
URN: urn:nbn:se:uu:diva-382389DOI: 10.1186/s13321-019-0348-5ISI: 000463589200001PubMedID: 30941533OAI: oai:DiVA.org:uu-382389DiVA, id: diva2:1307194
Funder
Swedish Research CouncileSSENCE - An eScience CollaborationAvailable from: 2019-04-26 Created: 2019-04-26 Last updated: 2019-04-26Bibliographically approved

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Jespers, WillemEsguerra, MauricioÅqvist, JohanGutiérrez-de-Terán, Hugo
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