1. Introduction
The importance of EFGR in driving tumor genesis in NSCLC, as well as other types
of cancer, has been clinically validated and inhibitors of EGFR have been approved
for treatment of a series of cancer. ATP competitive inhibitors of the TKD domain
include gefitinib (Iressa®).1 However, mutations in the tyrosine kinase domain have
been shown to be strongly associated with the response of NSCLC patients to
gefitinib treatment. To improve the understanding of the acquired resistance
mechanism, molecular modeling is a good tool for this purpose. Accurate
computation of free energies of binding remains a key challenge for computer-aided
drug design.2-3
2. Results and Discussion
In this work, we performed simulations of three different point mutation of EGFR in
complex with gefitinib: L858R, T790M and R831H.
The first two mutations are the most frequent in patients
with NSCLC; L858R was found to be a responsive
mutation and T790M a resistance mutation, confirming
experimental data. The results of R831H (Fig.1), a less
common and recently discovered mutation, show a
good responsive behaviour but less than L858R. The
agreement of our results with clinical data proves the
reliability of molecular simulations to predict the
behavior of this kind of complex.
