Drug specificity and affinity are encoded in the probability of cryptic pocket opening in myosin motor domains.

ABSTRACT: The design of compounds that can discriminate between closely related target proteins remains a central challenge in drug discovery. Specific therapeutics targeting the highly conserved myosin motor family are urgently needed as mutations in at least six of its members cause numerous diseases. Allosteric modulators, like the myosin-II inhibitor blebbistatin, are a promising means to achieve specificity. However, it remains unclear why blebbistatin inhibits myosin-II motors with different potencies given that it binds at a highly conserved pocket that is always closed in blebbistatin-free experimental structures. We hypothesized that the probability of pocket opening is an important determinant of the potency of compounds like blebbistatin. To test this hypothesis, we used Markov state mode

SUBMITTER: Meller A 

PROVIDER: S-EPMC9995120 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature