Rigid Scaffolds Are Promising for Designing Macrocyclic Kinase Inhibitors.

ABSTRACT: Macrocyclic kinase inhibitors (MKIs) are gaining attention due to their favorable selectivity and potential to overcome drug resistance, yet they remain challenging to design because of their novel structures. To facilitate the design and discovery of MKIs, we investigate MKI rational design starting from initial acyclic compounds by performing microsecond-scale atomistic simulations for multiple MKIs, constructing an MKI database, and analyzing MKIs using hierarchical cluster analysis. Our studies demonstrate that the binding modes of MKIs are like those of their corresponding acyclic counterparts against the same kinase targets. Importantly, within the respective binding sites, the MKI scaffolds retain the same conformations as their corresponding acyclic counterparts, demonstrating the

SUBMITTER: Zhao Z 

PROVIDER: S-EPMC10425998 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature