Yudhi Dwi Kurniawan, Faris Hermawan, Lathifah Puji Hastuti, Lala Adetia Marlina, Teni Ernawati, Salahuddin, Muhammad Alfin Sulmantara, Nicky Rahmana Putra
Epidermal growth factor receptor (EGFR) inhibitors are commonly utilized in treating cancers such as non-small cell lung cancer (NSCLC). However, the emergence of resistance often reduces their long-term effectiveness, prompting an urgent need for novel inhibitors. In this study, we designed and assessed a series of amino acid-functionalized 2,5-diketopiperazine (DKP) derivatives as potential EGFR inhibitors using molecular docking and dynamics simulations. Ten analogs were docked against the EGFR kinase domain (PDB ID: 1M17), exhibiting binding energies ranging from −8.88 to −10.26 kcal/mol. For comparison, Erlotinib and Doxorubicin showed binding energies of −7.05 and −10.23 kcal/mol, respectively. Notably, compound 10 demonstrated a lower binding energy than both reference compounds, indicating strong binding affinity and favorable interactions with key residues such as Met769. Furthermore, molecular dynamics simulations over 100 nanoseconds, including analyses of RMSD, RMSF, radius of gyration (Rg), and hydrogen bonding patterns, revealed that compounds 3, 5, and 10 maintained structural stability and consistent interactions throughout the simulations. These findings highlight the potential of amino acid-functionalized 2,5-DKP-based compounds as next-generation EGFR inhibitors, setting the stage for future experimental validation and therapeutic exploration. © 2025 Wiley-VCH GmbH.
Research Center for Pharmaceutical Ingredient and Traditional Medicine, National Research and Innovation Agency (BRIN), Banten, Tangerang Selatan, 15314, Indonesia; Graduate School, Universitas Padjadjaran, Bandung, Indonesia; Research Center for Computing, National Research and Innovation Agency (BRIN), Cibinong, Bogor, 16911, Indonesia; State University of Semarang, Sekaran, Gunung Pati, Central Java, Semarang, 50229, Indonesia; Faculty of Engineering Technology and Science, Higher College of Technology (HCT), Abu Dhabi, United Arab Emirates
