Open AccessDrugging the undruggable: a computational chemist's view of KRASG12C
Author(s) -
Michael S. Bodnarchuk,
Doyle J. Cassar,
Jason G. Kettle,
Graeme R. Robb,
Richard A. Ward
Publication year - 2021
Publication title -
rsc medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.754
H-Index - 55
ISSN - 2632-8682
DOI - 10.1039/d1md00055a
Subject(s) - context (archaeology) , kras , chemistry , chemist , computer science , covalent bond , computational biology , combinatorial chemistry , mutation , biochemistry , biology , organic chemistry , paleontology , gene
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.