Drugging the undruggable: a computational chemist's view of KRAS^G12C.

ABSTRACT: In recent years, the emergence of targeted covalent inhibitors which bind to the G12C mutant of KRAS have offered a solution to this previously intractable target. Inhibitors of KRAS^G12C tend to be structurally complex, displaying features such as atropisomerism, chiral centres and a reactive covalent warhead. Such molecules result in lengthy and challenging syntheses, and as a consequence critical decisions need to be made at the design level to maximise the chances of success. Here we take a retrospective look into how computational chemistry can help guide and prioritise medicinal chemistry efforts in the context of a series of conformationally restricted tetracyclic quinolines.

SUBMITTER: Bodnarchuk MS 

PROVIDER: S-EPMC8128063 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature