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A computational approach to explore and identify potential herbal inhibitors for the p21-activated kinase 1 (PAK1)
Md Shahinozzaman1,2, Takahiro Ishii2, Sinthyia Ahmed3
1PAK Research Center, University of the Ryukyus, Okinawa, Japan.
Abstract:
The oncogenic kinase PAK1 (p21-activated kinase 1) is involved in developing many diseases including cancers, neurofibromatosis, Alzheimer's disease, diabetes (type 2), and hypertension. Thus, it is thought to be a prominent therapeutic target, and its selective inhibitors have a huge market potential. Recently, herbal PAK1 inhibitors have gained immense interest over synthetic ones mainly due to their non-toxic effects. Till date, many herbal compounds have been suggested to inhibit PAK1, but their information on selectivity, bioavailability, ADMET (absorption, distribution, metabolism, excretion, and toxicity) properties, and molecular interactions with PAK1 has not been explored. Hence, this study was designed with computational approaches to explore and identify the best herbal PAK1-blockers showing good ADMET properties, druggable features and binding affinity with PAK1. Herbal inhibitors reported here were initially filtered with Lipinski's rule of five (RO5). Then, molecular docking between these inhibitors and PAK1 catalytic sites was performed using AutoDock Vina and GOLD suite to determine the binding affinity and interactions. Finally, 200 ns molecular dynamics (MD) simulations on three top-ranked inhibitors including cucurbitacin I (C-I), nymphaeol A (NA), and staurosporine (SPN) were carried out. The binding free energies and interactions revealed that NA can strongly bind with the PAK1 catalytic cleft. PASS prediction and ADMET profiling supported that NA is appeared to be a more selective and safer inhibitor than C-I and SPN. These results conform to the previous experimental evidences, and therefore, NA from Okinawa propolis could be a promising inhibitor for treating PAK1-dependent illnesses.Communicated by Ramaswamy H. Sarma.
Insights
Nymphaeol A, a herbal compound, shows strong binding and favorable safety profiles as a potential inhibitor for the oncogenic kinase PAK1, offering a promising therapeutic avenue for various diseases. This discovery highlights natural compounds as safer alternatives to synthetic drugs.
Area of Science:
- Biochemistry
- Pharmacology
- Computational Biology
Background:
- The oncogenic kinase PAK1 is implicated in numerous diseases, including cancers and neurodegenerative disorders, making it a significant therapeutic target.
- Herbal inhibitors of PAK1 are gaining interest due to their non-toxic profiles, but their properties require thorough investigation.
- Limited data exists on the selectivity, bioavailability, ADMET properties, and molecular interactions of proposed herbal PAK1 inhibitors.
Purpose of the Study:
- To computationally identify and explore potent herbal inhibitors of PAK1 with favorable ADMET properties and druggable features.
- To evaluate the binding affinity and molecular interactions of selected herbal compounds with the PAK1 catalytic site.
- To assess the safety and selectivity profiles of top-ranked herbal PAK1 inhibitors.
Main Methods:
- Initial filtering of herbal inhibitors using Lipinski's Rule of Five (RO5).
- Molecular docking simulations using AutoDock Vina and GOLD suite to assess binding affinity and interactions with PAK1.
- 200 ns molecular dynamics (MD) simulations for top-ranked inhibitors (cucurbitacin I, nymphaeol A, staurosporine) to analyze binding free energies and interactions.
- PASS prediction and ADMET profiling for safety and selectivity assessment.
Main Results:
- Nymphaeol A (NA) demonstrated strong binding affinity within the PAK1 catalytic cleft.
- Computational analysis indicated that NA possesses superior selectivity and safety compared to cucurbitacin I (C-I) and staurosporine (SPN).
- PASS prediction and ADMET profiling supported NA's potential as a safer inhibitor.
Conclusions:
- Nymphaeol A, derived from Okinawa propolis, is identified as a promising candidate for inhibiting PAK1.
- The findings align with existing experimental evidence, supporting NA's therapeutic potential for PAK1-dependent illnesses.
- Herbal compounds, like NA, represent a viable and safer alternative for developing novel therapeutics targeting PAK1.
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