Systems Biology and Molecular Dynamics Approach for Identifying Synergistic Drug Combinations in Cancer Therapy

An important target in cancer treatment is Epidermal Growth Factor Receptor (EGFR), and small-molecule inhibitors that bind to its active site can greatly reduce its activity. This study investigated the potential of drug conjugation for targeted cancer therapy by analyzing the EGFR network. It evaluates the interaction of Doxorubicin and Gemcitabine with EGFR, and conducts a similarity search using FDA-approved conjugate drugs. After initial screening through deduplication, which reduced an initial set of 89 compounds to 46 unique candidates, molecular docking and Density Functional Theory (DFT) calculations were performed. Based on binding affinity and DFT energy values, four compounds (PubChem IDs 422288, 434871, 44458986 and 166149926) were identified as promising EGFR inhibitors. These compounds demonstrated strong binding potential (−8.9 kcal to −9.4 kcal/mol) and stable electronic properties (−2861.60 atomic units to −2732.72 atomic units), making them viable candidates for further investigation in EGFR-targeted therapies. Docking was further validated by re-docking the compounds with the protein which showed a similar range of docking scores. Further EGFR-ligand complexes were analyzed using molecular dynamics simulations for 500 ns and energy decomposition to determine their binding stability and key interactions. The ligand 434871 showed stable binding in RMSD, RMSF and SASA studies. However, ligand 434871 showed slightly more conformational flexibility. The most favorable binding free energy (−36.89 kcal/mol) was observed for ligand 434871 through MM/GBSA calculations. Overall, these findings demonstrate the ability of these compounds to inhibit EGFR protein, which plays a major role in cancer growth and progression. These intriguing in silico results highlight the necessity for additional in vitro and in vivo studies to confirm the usefulness of these drugs in real biological systems.