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Updated: Sep 15, 2025
Quantitative Structure-Activity Relationship, Activity Prediction, and Molecular Dynamics of Non-nucleotide Reverse Transcriptase Inhibitors
Published on: May 9, 2025
Investigation of potential KRASG12D inhibitors: a comparative study between MRTX1133 and natural compounds via
Safiye Merve Bostancioglu1, Ahmet Acar2
1Department of Biology, Faculty of Arts and Sciences, Marmara University, Goztepe Campus, Goztepe, Istanbul, 34722, Turkey. mervebostancioglu@marun.edu.tr.
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.
Insights
Two natural compounds, NPA019556 and NPA032945, show promise as KRASG12D inhibitors. These compounds exhibit strong binding and stable interactions, offering potential for new cancer therapies targeting KRAS mutations.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- The RAS protein family (KRAS, NRAS, HRAS) is crucial in oncogenesis, regulating cellular processes.
- Directly targeting RAS proteins therapeutically remains a significant challenge in cancer treatment.
- Targeting specific mutations like KRASG12D with natural compounds presents a promising therapeutic avenue.
Purpose of the Study:
- To investigate the potential of natural products to inhibit the oncogenic KRASG12D mutant.
- To identify novel KRASG12D inhibitors from a natural compound library using computational methods.
Main Methods:
- Structure-based virtual screening of a natural compound library.
- Molecular dynamics simulations to analyze binding interactions.
- Post-simulation analyses including Dynamic Cross-Correlation Matrix and Principal Component Analysis.
Main Results:
- Two natural compounds, NPA019556 and NPA032945, exhibited strong and stable binding to KRASG12D.
- These compounds outperformed the known inhibitor MRTX1133 in binding efficacy.
- Analysis revealed distinct dynamic behaviors in switch I and switch II regions upon compound binding.
Conclusions:
- NPA019556 and NPA032945 are identified as potent and specific inhibitors of KRASG12D.
- These natural compounds demonstrate significant therapeutic potential for KRAS-driven cancers.
- Further development of these compounds could lead to novel targeted cancer therapies.
