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
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 GT...
| Autores: | , |
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| Tipo de recurso: | artículo |
| Fecha de publicación: | 2022 |
| País: | España |
| Institución: | Universitat Politècnica de Catalunya (UPC) |
| Repositorio: | UPCommons. Portal del coneixement obert de la UPC |
| Idioma: | inglés |
| OAI Identifier: | oai:upcommons.upc.edu:2117/376281 |
| Acceso en línea: | https://hdl.handle.net/2117/376281 https://dx.doi.org/10.3390/ijms232213865 |
| Access Level: | acceso abierto |
| Palabra clave: | Molecular dynamics Oncogenes KRAS-G12D oncogen Benzothiadiazine derivatives Dynamic drugging pockets Drug design KRAS oncogenes Dinàmica molecular Oncogens Àrees temàtiques de la UPC::Física |
| Sumario: | 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 conducted yet on Mg2+ when associated with KRAS. Herein, through microsecond scale molecular dynamics simulations, we found that Mg2+ 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-Mg2+ ternary complex. Overall, we provide two brand new druggable pockets located on KRAS-G12D and suitable strategies for its inhibition. |
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