Abstract
The anomalous binding modes of five highly similar fragments of TIE2 inhibitors, showing three distinct binding poses, are investigated. We report a quantitative rationalization for the changes in binding pose based on molecular dynamics simulations. We investigated five fragments in complex with the transforming growth factor β receptor type 1 kinase domain. Analyses of these simulations using Grid Inhomogeneous Solvation Theory (GIST), pKA calculations, and a tool to investigate enthalpic differences upon binding unraveled the various thermodynamic contributions to the different binding modes. While one binding mode flip can be rationalized by steric repulsion, the second binding pose flip revealed a different protonation state for one of the ligands, leading to different enthalpic and entropic contributions to the binding free energy. One binding pose is stabilized by the displacement of entropically unfavored water molecules (binding pose determined by solvation entropy), ligands in the other binding pose are stabilized by strong enthalpic interactions, overcompensating the unfavorable water entropy in this pose (binding pose determined by enthalpic interactions). This analysis elucidates unprecedented details determining the flipping of the binding modes, which can elegantly explain the experimental findings for this system.
Highlights
Structure-based drug design is used to guide drug discovery with the help of a known three-dimensional structure of a potential drug target
One binding pose is stabilized by the displacement of entropically unfavored water molecules, ligands in the other binding pose are stabilized by strong enthalpic interactions, overcompensating the unfavorable water entropy in this pose
To capture the complete thermodynamics of the ligand binding process including the flip in the binding pose from compound C to D (Figure 1) we have to use an amalgam of analyses tools
Summary
Structure-based drug design is used to guide drug discovery with the help of a known three-dimensional structure of a potential drug target. The correct prediction of small molecule binding to a target is essential for the success of structure-based drug design projects. The most common way to experimentally determine binding modes is by X-ray crystallography. It is essential to know how often a structural revalidation of the binding modes by X-ray crystallography is required. There is no simple answer to this question.[1] Small molecules, e.g. fragments, may readily change their binding modes upon larger modifications (for fragments already an absolute small modification can be large relative to the fragment size) but on the other hand may preserve key binding interactions when bound to binding site hot-spots.[2] Nonadditive behavior of substituents in structure−
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