Thermodynamics and mechanism of afatinib–EGFR binding through a QM/MM approach

We compute the different thermodynamic interaction parameters between afatinib, a tyrosine kinase inhibitor, and the epidermal growth factor receptor (EGFR) protein found in the cell membrane of lung epidermal cells and primarily responsible for non-small cell lung cancer (NSCLC). We compare the interaction entropy component (-<i>T</i>Δ<i>S</i>) of the binding energy obtained through normal mode or Nmode analysis (NMA), interaction entropy (IE), and C2 methods. We observe a much closer value of the binding free energy of the hydrated complex (-19.86 kcal mol^-1) with the experimental value (about -13.00 kcal mol^-1) compared to those obtained through newly developed IE and C2 methods (about -32.96 kcal mol^-1 and -35.47 kcal mol^-1, respectively). The present study with molecular mechanics/Poisson-Boltzmann surface area (MM/PBSA) shows the standard deviation of binding energies (<i>σ</i> _IE = 3.54 kcal mol^-1) which is an indication of the convergence of binding entropy with a lower value of energy. Advancement in structural biology with appropriate simulation techniques is an essential feature to meet challenges in covalent drug discovery as such drugs have been used to treat various types of cancers.