Theodrenaline

Cancer has become a prevalent disease that imposes a huge burden on society and the scientific community, and the worst-case scenario has evolved nowadays due to its resistance profiles. Lung cancer comes first in diagnosis and death and is gender-neutral, causing 1.8 million deaths yearly. In this study, we have collected 24 target proteins of lung cancer that are actively participating in its development, and the idea behind it was to identify a drug candidate that can show multitargeted efficacy against all. We performed molecular docking with HTVS, SP and XP sampling algorithms and MM\GBSA-based pose fileting, which helped to identify Theodrenaline (DB12927) as a multitargeted inhibitor with docking scores ranging from -5.1 to -13.6 Kcal/mol. Interaction fingerprint analysis identified 30LEU, 23VAL, 20LYS, and 17ASP as key residues, emphasizing hydrophobic interactions. Compared to Theodrenaline, the FDA-approved drug Crizotinib showed less promising results. Pharmacokinetic assessments, DFT calculations, and 5 ns WaterMap computations supported Theodrenaline's drug-like properties and computational efficacy. Additionally, a 100 ns MD simulation using the SPC water model (NPT ensemble) showed minimal deviations (<2 Å) and strong intermolecular interactions, while Crizotinib exhibited lower stability and weaker interactions. Theodrenaline exhibited notable cytotoxic effects on the A549 cancer cell line, with ∼58 % and 41 % cytotoxicity observed after 24 h and 48 h of treatment at a 10 μM concentration, respectively. Despite some cytotoxicity on normal cells at higher concentrations, theodrenaline was less toxic to these cells than cancer cells, as confirmed by microscopic analysis. Theodrenaline also demonstrated potent antioxidant activity, surpassing Paclitaxel and ascorbic acid, with 62 % DPPH activity at 10 μM. Furthermore, theodrenaline downregulated NFκB p65 protein expression by 35 % at 1 μM after 24 h, showing similar effectiveness to Paclitaxel at lower concentrations. Comprehensive computational and experimental studies support Theodrenaline as a promising multitargeted drug that outperforms FDA-approved compounds in overcoming lung cancer resistance-however, in vivo studies are recommended for further validation.