The discovery of mutations within the
kinase domain of the
epidermal growth factor receptor (EGFR) gene has enabled a new era of targeted
therapy in
non-small cell lung cancer (NSCLC). Drugs belonging to the family of
tyrosine kinase inhibitors (TKIs) are designed to bind
ATP binding cleft, anyway, the occurrence of aminoacidic mutations decreases the effectiveness of the antitumoral treatment. Despite many efforts has been already made, the impact of the mutations on conformation and stability of EGFR-
ATP complexes is still not fully understood. Therefore, we investigated the effect of mutations that leads to changes in Michaelis-Menten constant (Km) using dynamic docking simulations. We focused on six different EGFR forms in relation to different mutation states, then we found a good correlation between the calculated
ATP affinities and Km values. Moreover, since dynamic switching of TK-EGFR from the inactive towards the active state is known to regulate the
kinase activity, we observed that
ATP induces the inwards movement of the αC-helix with the Lys745 close to Glu762 in all cases. This means that
ATP binding should be the first step in promoting the conformational shift to the active state. Finally, we highlighted for the first time the key contribution of water hydrogen bond and water-bridge networks in the modulation of
ATP affinity. The identified mutant-specific
ATP binding patterns and conformational features could be much useful to guide
cancer therapy and develop more
personalized medicine. Communicated by Ramaswamy H. Sarma.