Pathways and mechanism of MRTX1133 binding to KRAS G12D elucidated by molecular dynamics simulations and Markov state...

Area of Science:

• Oncology
• Computational Chemistry
• Molecular Biology

Background:

• KRAS G12D mutations drive various cancers, making KRAS G12D inhibitors a key therapeutic strategy.
• MRTX1133 is a potent KRAS G12D inhibitor in clinical trials, but its binding mechanism is unknown.
• Understanding binding pathways is crucial for structure-based drug design against KRAS G12D.

Purpose of the Study:

• To elucidate the binding pathways and mechanism of MRTX1133 to KRAS G12D using molecular dynamics simulations.
• To identify key residues involved in MRTX1133 recognition and binding.
• To provide insights for optimizing KRAS G12D-targeted anticancer therapies.

Main Methods:

• Unbiased molecular dynamics (MD) simulations were employed to observe spontaneous MRTX1133 binding to KRAS G12D.
• Markov state models (MSM) analysis was used to reveal kinetically metastable states and potential binding pathways.
• Molecular mechanics with the generalized Born surface area (MM/GBSA) method identified key residues crucial for binding.

Main Results:

• MRTX1133 successfully associated with KRAS G12D in 6 out of 42 independent MD simulations (totaling 99 μs).
• MSM analysis identified potential pathways and metastable states for MRTX1133 binding.
• MM/GBSA analysis pinpointed 8 key residues essential for MRTX1133 recognition and tight binding.

Conclusions:

• This study provides novel insights into the dynamic process of MRTX1133 binding to KRAS G12D.
• The identified binding pathways and key residues can inform future structure-based drug design for KRAS G12D inhibitors.
• These findings contribute to the development of more effective anticancer therapies targeting KRAS G12D mutations.