Prediction of fold resistance for inhibitors of EGFR using all-atom molecular dynamics simulations

COMP 256

Trent E. Balius, and Robert C. Rizzo, Department of Applied Mathematics and Statistics, Stony Brook University, Stony Brook, NY 11790-3600
The tyrosine kinase domain (TKD) of Epidermal Growth Factor Receptor (EGFR) is an important and validated drug target for many types of cancers including non-small cell lung (NSCL) and breast. Despite the clinical success of ATP-competitive inhibitors such as erlotinib, which target EGFR, drug resistance mutations in the TKD can occur which alters drug potency. Here, in an effort to characterize fold resistance, we describe computational structural models and results from molecular dynamics simulations for inhibitor complexes with several EGFR variants including wild type, L858R (cancer causing mutant), and L858R&T790M (drug resistance mutant). Free energies of binding, per-residue contributions to binding, and structural differences which occur as a result of the mutations for different inhibitors will be discussed.

Poster Session
6:00 PM-8:00 PM, Tuesday, August 18, 2009 Walter E. Washington Convention Center -- Ballroom A, Poster

Division of Computers in Chemistry

The 238th ACS National Meeting, Washington, DC, August 16-20, 2009