Microsecond Molecular Dynamics Simulation to Gain Insight Into the Binding of MRTX1133 and Trametinib With KRASG12D Mutant Protein for Drug Repurposing

ABSTRACT The Kirsten Rat Sarcoma (KRAS) G12D mutant protein is a primary driver of pancreatic ductal adenocarcinoma, necessitating the identification of targeted drug molecules. Repurposing of drugs quickly finds new uses, speeding treatment development. This study employs microsecond molecular dynamics simulations to unveil the binding mechanisms of the FDA‐approved MEK inhibitor trametinib with KRAS G12D , providing insights for potential drug repurposing. The binding of trametinib was compared with clinical trial drug MRTX1133, which demonstrates exceptional activity against KRAS G12D , for better understanding of interaction mechanism of trametinib with KRAS G12D . The resulting stable MRTX1133‐KRAS G12D complex reduces root mean square deviation (RMSD) values, in Switch I and II domains, highlighting its potential for inhibiting KRAS G12D . MRTX1133's robust interaction with Tyr64 and disruption of Tyr96‐Tyr71‐Arg68 network showcase its ability to mitigate the effects of the G12D mutation. In contrast, trametinib employs a distinctive binding mechanism involving P‐loop, Switch I and II residues. Extended simulations to 1 μs reveal sustained network interactions with Tyr32, Thr58, and GDP, suggesting a role of trametinib in maintaining KRAS G12D in an inactive state and impede the further cell signaling. The decomposition binding free energy values illustrate amino acids' contributions to binding energy, elucidating ligand–protein interactions and molecular stability. The machine learning approach reveals that van der Waals interactions among the residues play vital role in complex stability and the potential amino acids involved in drug–receptor interactions of each complex. These details provide a molecular‐level understanding of drug binding mechanisms, offering essential knowledge for further drug repurposing and potential drug discovery.