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Identification of Therapeutic Compounds Targeting Phosphatidylinositol 3-Kinase (PI3K) Through Molecular Docking,
Jehad Zuhair Tayyeb1, Imren Bayıl2, Taha Alqahtani3
1Division of Clinical Biochemistry, Department of Basic Medical Sciences, College of Medicine, University of Jeddah, Jeddah 23890, Saudi Arabia.
Abstract:
Cancer is one of the leading causes of death worldwide and characterized by uncontrolled cell proliferation. The phosphatidylinositol 3-kinase (PI3K) is an enzyme, which is essential for regulating cell growth and survival, is often dysregulated in tumors. Currently available PI3K inhibitors (like Duvelisib) have significant side effects, highlighting the need for safer therapeutics. Gallic acid, a natural phenolic compound with remarkable antineoplastic properties, showcases a promising scaffold for drug development. The aim of this study is to identify potential PI3K inhibitors from gallic acid derivatives using advanced computational techniques such as PASS prediction, molecular docking, ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) analysis, density functional theory (DFT) calculations, and molecular dynamics (MD) simulations. Five derivatives 21, 37, 44, 68 and 75 were selected based on their predicted antineoplastic activity among 90 derivatives, as well as the control drug Duvelisib. Compound 68 proved to be the most promising candidate, exhibiting strong binding affinity to the PI3K receptor, forming multiple hydrogen bonds with key residues, and showing stable interactions over 500 ns MD simulation. ADMET analysis revealed that compound 68 had favorable pharmacokinetic properties. Compound 21 also showed strong binding affinity but exhibited limitations in its pharmacokinetic profile. This study aims to improve our understanding of ligand-protein dynamics in PI3K inhibition and highlight the potential of gallic acid derivatives in developing safer and more effective PI3K inhibitors for cancer therapy. Our results support further experimental validation of compound 68 and suggest that gallic acid derivatives could contribute to the development of safer therapies.
Insights
Researchers identified promising gallic acid derivatives as potential new cancer drugs. Compound 68 shows strong potential as a safer phosphatidylinositol 3-kinase (PI3K) inhibitor, warranting further investigation for cancer therapy.
Area of Science:
- Medicinal Chemistry
- Computational Drug Discovery
- Oncology
Background:
- Cancer, a leading cause of death, involves uncontrolled cell proliferation often driven by dysregulated phosphatidylinositol 3-kinase (PI3K).
- Existing PI3K inhibitors have significant side effects, necessitating the development of safer alternatives.
- Gallic acid, a natural compound, offers a promising scaffold for novel antineoplastic drug development.
Purpose of the Study:
- To identify potential PI3K inhibitors from gallic acid derivatives using computational methods.
- To evaluate the efficacy and safety profiles of selected gallic acid derivatives.
- To explore the potential of these derivatives in developing safer cancer therapeutics.
Main Methods:
- PASS prediction for antineoplastic activity screening.
- Molecular docking to assess binding affinity to the PI3K receptor.
- ADMET analysis for pharmacokinetic and toxicity profiling.
- Density Functional Theory (DFT) calculations and Molecular Dynamics (MD) simulations for stability and interaction analysis.
Main Results:
- Five gallic acid derivatives (21, 37, 44, 68, 75) were selected from 90 candidates based on predicted activity.
- Compound 68 demonstrated strong binding affinity to PI3K, stable interactions via MD simulations, and favorable ADMET properties.
- Compound 21 also showed high binding affinity but had pharmacokinetic limitations.
- Compound 68 emerged as the most promising candidate for further development.
Conclusions:
- Gallic acid derivatives show significant potential for developing safer and more effective PI3K inhibitors.
- Compound 68 is a strong candidate for experimental validation in cancer therapy.
- This study enhances understanding of PI3K inhibition and highlights a new avenue for cancer drug discovery.
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