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Target-Specific Potency and Drug-Ability Profile of Flavonoids Against Lung Cancer: An Integrative Multi-Omics
Ali M Alaseem1, Glowi Alasiri2, Arockia Babu Marianesan3
1Department of Pharmacology, College of Medicine, Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh, Saudi Arabia.
Abstract:
Since lung cancer accounts for approximately 20% of cancer-related fatalities globally, it is one of the most common and deadly cancers, necessitating the discovery of innovative, potent, and less toxic treatment agents as imperative. Opportunistically, phytoflavonoids (PFs), a specific class of phytochemicals, display promising anticancer activity through their multimodal apoptosis-inducing properties. Based on existing evidence, the present study employs an integrative multi-omics approach to assess the target-specific binding efficacy and drug-ability outlines of PFs against lung cancer. We selected two of the most likely lung cancer targets using the core part of PFs: carbonic anhydrase IX (PDB ID: 3DAZ) and poly(A) binding protein cytoplasmic 1 (PDB ID: 3KUJ). Another two key targets, glutathione S-transferase P1 (PDB ID: 3GSS) and 17β-hydroxysteroid dehydrogenase 1 (HSD17B1, 3HB4), were also included in our study based on recent literature. The potency of 66 PFs against four targets was assessed through a molecular docking study using PyRx 0.8-AutoDock 4.2 software. PF15, PF43, PF6, and PF26 were the lead candidates. Further, physicochemical profiles through standard Lipinski rule of five parameters and toxicity and drug-ability profiles suggested that PF43 (naringenin) is the most ideal lead candidate among them. Molecular dynamics (MD) simulation studies were performed at 200 ns to observe the kinetic behaviors of CA9-PF43 and CA9-U-1014 docking complexes along with the calculated free energy through the MM/PBSA method. From both analyses, PF43 showed higher stability and lower free energy, expressing its potency over the standard drug. We also investigated the structure-activity relationship and frontier molecular orbitals to highlight the drug chemistry of lead PFs. The integrative multi-omics investigation suggested that using PF43 for lung cancer treatment could increase the chances of experimental success. Overall, the systematic computational analyses provide a platform for lead identification and pave the way for precision phytotherapy in current drug discovery.
Insights
Phytoflavonoids show promise for lung cancer treatment. Naringenin (PF43) demonstrated superior binding and stability against key lung cancer targets, suggesting its potential as a novel therapeutic agent.
Area of Science:
- Computational chemistry and pharmacology
- Phytochemical drug discovery
- Oncology research
Background:
- Lung cancer is a leading cause of cancer mortality worldwide, necessitating novel and less toxic treatments.
- Phytoflavonoids (PFs) exhibit anticancer properties via apoptosis induction.
- Identifying effective PFs against lung cancer targets is crucial for drug development.
Purpose of the Study:
- To assess the binding efficacy and drug-likeness of phytoflavonoids against lung cancer targets using an integrative multi-omics approach.
- To identify potent phytoflavonoid candidates for lung cancer therapy.
- To evaluate the stability and potency of lead candidates through molecular dynamics simulations.
Main Methods:
- Molecular docking studies of 66 phytoflavonoids against four selected lung cancer targets: carbonic anhydrase IX (3DAZ), poly(A) binding protein cytoplasmic 1 (3KUJ), glutathione S-transferase P1 (3GSS), and 17β-hydroxysteroid dehydrogenase 1 (3HB4).
- Physicochemical profiling using Lipinski's rule of five, toxicity assessment, and drug-ability evaluation.
- 200 ns molecular dynamics (MD) simulations and MM/PBSA free energy calculations for the CA9-PF43 complex.
Main Results:
- Phytoflavonoids PF15, PF43, PF6, and PF26 emerged as lead candidates.
- PF43 (naringenin) was identified as the most ideal candidate based on physicochemical, toxicity, and drug-ability profiles.
- MD simulations and MM/PBSA analysis confirmed PF43's higher stability and lower binding free energy compared to a standard drug against CA9.
Conclusions:
- The integrative multi-omics approach successfully identified naringenin (PF43) as a highly promising phytoflavonoid for lung cancer treatment.
- PF43 demonstrates superior stability and potency against key lung cancer targets, warranting further experimental investigation.
- This study provides a computational platform for lead identification and supports the development of precision phytotherapy for lung cancer.
