Target‐Specific Potency and Drug‐Ability Profile of Flavonoids Against Lung Cancer: An Integrative Multi‐Omics Approach for Lead Identification

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.