Discovering and Targeting Dynamic Drugging Pockets of Oncogenic Proteins: The Role of Magnesium in Conformational Changes of the G12D Mutated Kirsten Rat Sarcoma-Guanosine Diphosphate Complex |
| |
Authors: | Zheyao Hu Jordi Marti |
| |
Affiliation: | Department of Physics, Polytechnic University of Catalonia-Barcelona Tech, B5-209 Northern Campus UPC, 08034 Barcelona, Catalonia, Spain |
| |
Abstract: | 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 Mg is closely related to the function of small GTPases, but no investigation has been conducted yet on Mg when associated with KRAS. Herein, through microsecond scale molecular dynamics simulations, we found that Mg plays a crucial role in the conformational changes of the KRAS-GDP complex. We 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 the KRAS-G12D-GDP-Mg ternary complex. Overall, we provide two brand new druggable pockets located on KRAS-G12D and suitable strategies for its inhibition. |
| |
Keywords: | benzothiadiazine derivatives drug design molecular dynamics KRAS oncogenes |
|
|