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Identification of Dietary Bioflavonoids as Potential Inhibitors against KRAS G12D Mutant-Novel Insights from
Prasanna Srinivasan Ramalingam1,2, Purushothaman Balakrishnan2, Senthilnathan Rajendran3
1Protein Engineering Lab, School of Biosciences and Technology, VIT University, Vellore 632014, Tamil Nadu, India.
Abstract:
The KRAS G12D mutation is very frequent in many cancers, such as pancreatic, colon and lung, and has remained undruggable for the past three decades, due to its smooth surface and lack of suitable pockets. Recent small pieces of evidence suggest that targeting the switch I/II of KRAS G12D mutant could be an efficient strategy. Therefore, in the present study, we targeted the switch I (residues 25-40) and switch II (residues 57-76) regions of KRAS G12D with dietary bioflavonoids in comparison with the reference KRAS SI/II inhibitor BI-2852. Initially, we screened 925 bioflavonoids based on drug-likeness properties, and ADME properties and selected 514 bioflavonoids for further studies. Molecular docking resulted in four lead bioflavonoids, namely 5-Dehydroxyparatocarpin K (L1), Carpachromene (L2), Sanggenone H (L3), and Kuwanol C (L4) with binding affinities of 8.8 Kcal/mol, 8.64 Kcal/mol, 8.62 Kcal/mol, and 8.58 Kcal/mol, respectively, in comparison with BI-2852 (-8.59 Kcal/mol). Further steered-molecular dynamics, molecular-dynamics simulation, toxicity, and in silico cancer-cell-line cytotoxicity predictions significantly support these four lead bioflavonoids as potential inhibitors of KRAS G12D SI/SII inhibitors. We finally conclude that these four bioflavonoids have potential inhibitory activity against the KRAS G12D mutant, and are further to be studied in vitro and in vivo, to evaluate their therapeutic potential and the utility of these compounds against KRAS G12D mutated cancers.
Insights
Dietary bioflavonoids show promise in inhibiting the KRAS G12D mutation, a target in pancreatic, colon, and lung cancers. These natural compounds offer a potential new therapeutic strategy for difficult-to-treat cancers.
Area of Science:
- Oncology
- Medicinal Chemistry
- Computational Biology
Background:
- The KRAS G12D mutation is prevalent in various cancers, including pancreatic, colon, and lung, and has historically been undruggable due to its structural characteristics.
- Targeting the switch I/II regions of KRAS G12D presents a potential therapeutic strategy.
Purpose of the Study:
- To identify dietary bioflavonoids that can inhibit the KRAS G12D mutant by targeting its switch I and switch II regions.
- To compare the efficacy of identified bioflavonoids with a known KRAS inhibitor, BI-2852.
Main Methods:
- Screening of 925 bioflavonoids based on drug-likeness and ADME properties.
- Molecular docking, steered-molecular dynamics, and molecular-dynamics simulations were employed.
- In silico toxicity and cancer cell line cytotoxicity predictions were performed.
Main Results:
- Four lead bioflavonoids (5-Dehydroxyparatocarpin K, Carpachromene, Sanggenone H, and Kuwanol C) were identified with significant binding affinities.
- These compounds demonstrated comparable or superior binding affinities to the reference inhibitor BI-2852.
- Computational predictions supported the potential of these bioflavonoids as KRAS G12D inhibitors.
Conclusions:
- The identified dietary bioflavonoids show potential as KRAS G12D inhibitors.
- Further in vitro and in vivo studies are warranted to evaluate their therapeutic potential against KRAS G12D-mutated cancers.
