4.7 Article

Towards Automated Binding Affinity Prediction Using an Iterative Linear Interaction Energy Approach

Journal

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 15, Issue 1, Pages 798-816

Publisher

MDPI AG
DOI: 10.3390/ijms15010798

Keywords

Automated binding free energy calculation; CYP 2D6; iterative LIE method; aryloxypropanolamines

Funding

  1. Innovative Medicines Initiative Joint Undertaking - European Union [115002]
  2. Netherlands Organization for Scientic Research, under ZonMW-Horizon Valorisation grant [93515507]

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Binding affinity prediction of potential drugs to target and off-target proteins is an essential asset in drug development. These predictions require the calculation of binding free energies. In such calculations, it is a major challenge to properly account for both the dynamic nature of the protein and the possible variety of ligand-binding orientations, while keeping computational costs tractable. Recently, an iterative Linear Interaction Energy (LIE) approach was introduced, in which results from multiple simulations of a protein-ligand complex are combined into a single binding free energy using a Boltzmann weighting-based scheme. This method was shown to reach experimental accuracy for flexible proteins while retaining the computational efficiency of the general LIE approach. Here, we show that the iterative LIE approach can be used to predict binding affinities in an automated way. A workflow was designed using preselected protein conformations, automated ligand docking and clustering, and a (semi-)automated molecular dynamics simulation setup. We show that using this workflow, binding affinities of aryloxypropanolamines to the malleable Cytochrome P450 2D6 enzyme can be predicted without a priori knowledge of dominant protein-ligand conformations. In addition, we provide an outlook for an approach to assess the quality of the LIE predictions, based on simulation outcomes only.

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