In silico design of a lipid-like compound targeting KRAS4B-G12D through non-covalent bonds
Huixia Lu, Zheyao Hu, Jordi Faraudo, Jordi Martı́ · Nanoscale · 2023
-1,2,4-benzothiadiazine, 3,4-dihydro-,1,1-dioxide). The proposed lipid-like molecule was found to lock KRAS4B-G12D in its GDP-bound state by adjusting the effector-binding domain to be blocked by the interface of the lipid bilayer. Meanwhile, it can tune GTP-bound KRAS4B-G12D to shift from the active orientation state to the inactive state. The proposed compound is also observed to stably accommodate itself in the prenyl-binding pocket of phosphodiesterase-δ, which impairs KRAS4B enrichment at the lipid bilayer, potentially reducing the proliferation of KRAS4B inside the cytoplasm and its anchoring at the bilayer. In conclusion, we report a potential inhibitor of KRAS4B-G12D with a lipid tail attached to a specific warhead, a compound which has not yet been considered for drugs targeting RAS mutants. Our work provides new ways to target KRAS4B-G12D and can also foster drug discovery efforts for the targeting of oncogenes of the RAS family and beyond.