Abstract
Target residence time plays a crucial role in the pharmacological activity of small molecule inhibitors. Little is known, however, about the underlying causes of inhibitor residence time at the molecular level, which complicates drug optimization processes. Here, we employ all-atom molecular dynamics simulations (~400 μs in total) to gain insight into the binding modes of two structurally similar p38α MAPK inhibitors (type I and type I½) with short and long residence times that otherwise show nearly identical inhibitory activities in the low nanomolar IC50 range. Our results highlight the importance of protein conformational stability and solvent exposure, buried surface area of the ligand and binding site resolvation energy for residence time. These findings are further confirmed by simulations with a structurally diverse short residence time inhibitor SB203580. In summary, our data provide guidance in compound design when aiming for inhibitors with improved target residence time.
Highlights
Target residence time plays a crucial role in the pharmacological activity of small molecule inhibitors
We have previously reported that among p38α MAPK inhibitors, the type I1⁄2 inhibitor regulatory-spine (R-spine) interaction is important for increased target residence time[26,27,28]
We anticipated that a better understanding of this process can provide general principles, which could be applied in the compound design process when aiming for improved target residence time
Summary
Target residence time plays a crucial role in the pharmacological activity of small molecule inhibitors. Earlier computational work investigating residence times has been mainly focusing on association/dissociation pathways of small molecules[10,11,12,13,14,15] These studies applied molecular dynamics (MD) simulations with enhanced sampling methods to enable relevant timescales required for the association/dissociation process[16,17,18,19]. We applied unbiased classical long timescale MD simulations to investigate behavior of the protein–ligand complex of p38α MAPK and two inhibitors, representing a first and a second generation dibenzosuberone-based inhibitor (type I and type I1⁄2) originated from Skepinone-L29 These compounds provide an excellent opportunity for detailed study, as they differ significantly in their residence time but are structurally similar and show comparable target inhibition, as demonstrated in biochemical assays with isolated enzymes. We identified protein conformational stability and water as decisive elements that demonstrated considerable differences among compounds with short and long residence time
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