Rapid and accurate ranking of binding affinities of epidermal growth factor receptor sequences with selected lung cancer drugs

Abstract

The epidermal growth factor receptor (EGFR) is a major target for drugs in treating lung carcinoma. Mutations in the tyrosine kinase domain of EGFR commonly arise in human cancers, which can cause drug sensitivity or resistance by influencing the relative strengths of drug and ATP-binding. In this study, we investigate the binding affinities of two tyrosine kinase inhibitors-AEE788 and Gefitinib-to EGFR using molecular dynamics simulation. The interactions between these inhibitors and the EGFR kinase domain are analysed using multiple short (ensemble) simulations and the molecular mechanics/Poisson-Boltzmann solvent area (MM/PBSA) method. Here, we show that ensemble simulations correctly rank the binding affinities for these systems: we report the successful ranking of each drug binding to a variety of EGFR sequences and of the two drugs binding to a given sequence, using petascale computing resources, within a few days.

Mechanism of Drug Efficacy Within the EGF Receptor Revealed by Microsecond Molecular Dynamics Simulation

“…The docking result for ATP is in agreement with the in vitro kinase activity experiment (10) that reveals a marked increase in the Michaelis constant (Km) for ATP in the L858R mutant as compared with the wild-type EGFR. The gefitinib result is also consistent with the binding assay experiment (33) and our previous simulation (14), in which gefitinib shows comparable binding affinities to both the wildtype and L858R mutant EGFRs. Consequently, the L858R-mutated EGFR prefers to bind gefitinib rather than ATP, which explains the efficacy of gefitinib for patients who are L858R mutation positive.…”

“…It is interesting to note that the substate of the L858R mutation, around (coordinates À30, 37) on the first 2 principal components, is only reached at about 3.4 ms; the same conformation was observed in one of our previous four 200 ns simulations (18), after only 100 ns simulation. Although multiple short (ensemble) simulations have been shown to explore local conformational space more effectively (14,25), long timescale simulations are needed for large-scale conformational changes such as ligand binding (26) and protein folding (27).…”

“…Proteins exist in different conformational substates that endow them with intrinsic degrees of flexibility. The conformational plasticity of the binding site allows multiple diverse ligands to bind at a single site (13), with differing binding affinities (14). Proteins are able to adjust the populations of these substates as they undergo such various binding events.…”

Computational study of EGFR inhibition: molecular dynamics studies on the active and inactive protein conformations

“…Molecular dynamics (MD) studies have in the past been used to elucidate dynamic aspects associated with protein kinases, including EGFR [7,[15][16][17][18]. Such simulations offer additional insight beyond the static, but nonetheless critical, snapshot as represented by an X-ray crystal structure.…”

Clinically driven design of multi-scale cancer models: the ContraCancrum project paradigm

“…Structural and energetic analyses indicate that converged sampling is reached with respect to the energy minima. A reasonable correlation has been obtained between the calculated drug-binding affinities and available experimental data [26]. The simulations reveal how interactions change as a result of mutations, and account for the molecular basis of drug efficacy.…”