In-silico investigation on drug likeness, toxicity and molecular docking on lung cancer proteins of metabolites from Indigofera hochstetteri Baker methanol extract

The I. hochstetteri methanolic extract has reported to contain 24 bioactive metabolites with significant antidiabetic, antimicrobial, anti-inflammatory, and anticancer activities specifically on human leukemia HL-60 cells. Current study explores the molecular docking potency of the I. hochstetteri metabolites against lung cancer-related apoptotic proteins and assesses their drug-likeness using SwissADME and toxicity by Protox-3. Molecular docking results indicate that the 24 metabolites demonstrate strong binding affinities with key lung cancer proteins: EGFR (1m17), EGFR (3g5z), and TP53 (8dc4). Notably, Campesterol exhibited high binding energies of -8.9, -7.5, and -9.4 kcal/mol for 1m17, 3g5z, and 8dc4, respectively. Other compounds, such as 6a,12a-Dihydro-6H-(1,3)dioxolo (5,6) benzofuro(3,2-c) chromen-3-ol and Rotenolone, also showed promising binding energies. Drug-likeness profiling revealed that 10 molecules fulfilled all major drug-likeness rules (Lipinski, Veber, Ghose, Muegge, Egan), while others showed minor deviations. ADME-Tox analyses highlighted high gastrointestinal absorption and less blood-brain barrier permeability for several candidates, with low predicted hepatotoxicity and favorable oral bioavailability. Notably, Rotenolone, though pharmacologically potent, exhibited significant predicted toxicity (LD₅₀ = 4 mg/kg; Class I), underscoring the need for cautious interpretation. Conversely, many lipophilic compounds like Phytol and Neophytadiene showed favorable pharmacokinetics and minimal predicted toxicity. Furthermore, synthetic accessibility scores suggested moderate to high feasibility for chemical synthesis of most compounds. This comprehensive analysis suggests that the metabolites from I. hochstetteri could be promising candidates for further development in lung cancer therapy, aligning with recent findings in the field of in silico drug discovery. Importantly, these findings not only highlight the therapeutic potential of I. hochstetteri metabolites but also give a foundation for further in vitro and in vivo validation, with the ultimate goal of advancing promising candidates toward preclinical and clinical development for lung cancer therapy.