Discovering and targeting dynamic drugging pockets of the oncogene KRAS-G12D

Abstract

Activated KRAS-G12D mutations are the one of most frequent oncogenic drivers in human cancers. Unfortunately, no therapeutic agent directly targeting KRAS-G12D has been clinically approved yet, with such mutated species remaining undrugged. Notably, cofactor Mg2+ is closely related to the function of small GTPases, but no investigation has been performed yet on Mg2+ when associated with KRAS. Herein, through microsecond scale molecular dynamics simulations we have found that Mg2+ plays a crucial role in the conformational changes of the KRAS-GDP complex. We have located two brand new druggable dynamic pockets exclusive to KRAS-G12D. Using the structural characteristics of these two dynamic pockets,we designed in silico the inhibitor DBD15-21-22, which can specifically and tightly target KRAS-G12D-GDP-Mg2+ ternary complex and we have verified that DBD15-21-22 is harmless for wild-type KRAS. Overall, we provide two brand new druggable pockets located on KRAS-G12D, as well as suitable strategies for KRAS-G12D inhibition.