Decisive role of water and protein dynamics in residence time of p38α MAP kinase inhibitors.

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 confirm

SUBMITTER: Pantsar T 

PROVIDER: S-EPMC8799644 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature