Integrated screening of Indonesian marine natural products as anticancer candidates through ADMET-clustering analysis, molecular docking, and molecular dynamics simulation

This research identifies potential anticancer agents by modulating the epidermal growth factor receptor (EGFR), a pivotal target in cancer therapeutics. Nowadays, finding effective and efficient EGFR inhibitors is essential because the currently available inhibitors have several side effects and have occasionally shown resistance. The emergence of EGFR protein mutations complicates this medical issue. Exploring the EGFR inhibitor candidates was conducted by employing deposited marine natural products in the Comprehensive Marine Natural Products Database (CMNPD). Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET)properties were applied for clustering analysis with approved inhibitors serving as the lead compounds. The efficacy of the inhibitor candidates was computationally evaluated by molecular docking and molecular dynamics simulation. A total of 13 compounds have resembled characteristics with approved EGFR inhibitors (Afatinib, Osimertinib, and Erlotinib), namely C19, C28, C83, C100, C116, C131, C143, C144, C147, C153, C162, C178, C185. Compounds C116 (Cadiolide A) and C162 (Cadiolide B) consistently showed the highest affinity with binding energies of -9.92 and -10.77 kcal/mol and -9.07 and -9.54 kcal/mol, respectively, against EGFR and EGFR mutants. The energies far exceed the stability of the complexes of approved EGFR inhibitors. The stability of the hit compound’s interaction was confirmed through molecular dynamics simulation, indicated by negligible fluctuations in the overall protein structure. The compound C116 and C162 are computationally promising candidates for EGFR inhibitors. The findings of this study can be examined for developing and searching for potential renewable EGFR inhibitor candidates.