Investigation of potential KRASG12D inhibitors: a comparative study between MRTX1133 and natural compounds via computational structural biology approaches.

Date

2025-07-12

Author

Bostancioglu, Safiye Merve
Acar, Ahmet

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This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

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Objective The RAS family, comprising KRAS, NRAS, and HRAS, plays a pivotal role in oncogenesis, dynamically regulating cellular processes through intricate cycling between active and inactive states. Despite recent advancements, direct therapeutic targeting of RAS proteins has proven challenging. Targeting KRASG12D with natural compounds offers a unique therapeutic potential, leveraging the structural diversity and bioactivity of natural compounds. In this study, we investigated the potential of natural products to target oncogenic KRASG12D mutant. Given the higher prevalence of KRASG12D mutations, our study employs structure-based virtual screening and molecular dynamics simulations to identify potential KRASG12D inhibitors within a natural compound library. Results Two natural compounds, NPA019556 and NPA032945, demonstrated strong and stable binding interactions with KRASG12D, surpassing the performance of known inhibitor MRTX1133. After post-molecular dynamics analyses, which encompass Dynamic Cross-Correlation Matrix and Principal Component Analysis, additional evidence suggests that the flexible switch I (residues 30–40) and switch II (residues 58–72) regions demonstrate greater anti-correlation in NPA019556 and NPA032945 compared to MRTX1133 complexed with KRASG12D. These findings highlight the promise of two natural compounds, NPA019556 and NPA032945, as specific KRASG12D inhibitors, paving the way for future and therapeutic development.

Subject Keywords

Natural products, KRASG12D, Structure-based virtual screening, Molecular dynamics simulation, MRTX1133, MRTX1133

URI

https://hdl.handle.net/11511/115249

Collections

Department of Biology, Article