Computational exploration of quercetin derivatives from Azadirachta indica leaf as threonine tyrosine kinase inhibitors for potential lung and pancreatic cancer treatment.

Lung and pancreatic adenocarcinomas account for substantial cancer-related mortality worldwide, with current therapeutic efficacy severely limited by the development of high drug resistance. Threonine tyrosine kinase (TTK) has emerged as both a therapeutic target and a critical prognostic marker in these malignancies, with elevated expression correlating strongly with poor clinical outcomes. Therefore, this study aimed to investigate natural quercetin derivatives from Azadirachta indica leaf as novel TTK inhibitors through comprehensive computational approaches. From initial TTK expression and survival analyses to subsequent Molecular docking, machine learning models predicted bioactivity estimation, quantum chemical calculations, molecular dynamics (MD) simulations, post-dynamics MM-PBSA calculations, and in silico toxicity profiling were performed to identify TTK inhibitors. TTK overexpression significantly correlated with diminished survival in both cancer types (hazard ratios: 1.5-2.0). Quercetin-3-rhamnoside, quercetin-3-glucoside, quercetin-3-O-galactoside, and quercetin-3-rutinoside demonstrated superior binding affinities (-9.5 to -11.089 kcal/mol) compared to control drug Luvixasertib (-8.869 kcal/mol), with enhanced electronic properties (electrophilicity index: 3.53-4.67 compared to control 2.70). Furthermore, Machine learning predictions demonstrated promising bioactivity (pIC50: 6.915-7.835), while 200 ns MD simulations confirmed structural stability with optimal RMSD (1.419-2.035 Å). Subsequently, MM-PBSA calculations revealed markedly favorable binding free energies for quercetin-3-rhamnoside and quercetin-3-glucoside (-33.104 and -32.676 kcal/mol) compared to control (-28.430 kcal/mol). Additionally, toxicity profiling revealed favorable safety profiles with no hepatotoxic, carcinogenic, or mutagenic potential for most derivatives. Therefore, Quercetin derivatives from A. indica leaf represent promising lead compounds for targeted TTK inhibitors in lung and pancreatic adenocarcinomas, highlighting their potential for further experimental validation against TTK.