L718Q mutant EGFR escapes covalent inhibition by stabilizing a non-reactive conformation of the lung cancer drug osimertinib

Callegari, Donatella; Ranaghan, Kara E.; Woods, Christopher; Minari, Roberta; Tiseo, Marcello; Mor, Marco; Mulholland, Adrian J.; Lodola, Alessio

doi:10.1039/c7sc04761d

Cited by 81 publications

(87 citation statements)

References 55 publications

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“…Generally, in practical investigations of reactivity, relative barriers (rather than absolute barriers) are important, 111, 112 e.g. to distinguish between possible mechanisms, to identify reactive conformations 113,114 , predict the effects of mutation, reactivity of alternative substrates or analyse chemo-, stereo-or regioselectivity. [101][102][103][104] However, limitations of DFT may prevent reliable predictions even for calculations of relative barriers.…”

Section: Acs Paragon Plus Environmentmentioning

confidence: 99%

Projector-Based Embedding Eliminates Density Functional Dependence for QM/MM Calculations of Reactions in Enzymes and Solution

Ranaghan

Shchepanovska

Bennie

et al. 2019

J. Chem. Inf. Model.

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Combined quantum mechanics/molecular mechanics (QM/MM) methods are increasingly widely utilized in studies of reactions in enzymes and other large systems. Here, we apply a range of QM/MM methods to investigate the Claisen rearrangement of chorismate to prephenate, in solution, and in the enzyme chorismate mutase. Using projector-based embedding in a QM/MM framework, we apply treatments up to the CCSD(T) level. We test a range of density functional QM/MM methods and QM region sizes. The results show that the calculated reaction energetics are significantly more sensitive to the choice of density functional than they are to the size of the QM region in these systems. Projector-based embedding of a wavefunction method in DFT reduced the 13 kcal/mol spread in barrier heights calculated at the DFT/MM level to a spread of just 0.3 kcal/mol, essentially eliminating dependence on the functional. Projector-based embedding of correlated ab initio methods provides a practical method for achieving high accuracy for energy profiles derived from DFT and DFT/MM calculations for reactions in condensed phases.well with the CI-NEB path and indicates that the reaction coordinate used here performs well for this reaction.Structures were taken from the corresponding solution or enzyme SCCDFTB/CHARMM22 MD stochastic boundary simulations (120 ps) of the model systems for use in adiabatic mapping calculations. For this, Jaguar 68 and Tinker 69 , linked by the interface program QoMMMa 70 , were used for QM and MM calculations, with electronic coupling between the two regions treated by including MM charges in the QM Hamiltonian.CHARMM27 Lennard-Jones parameters (for standard CHARMM27 atom types, see Table S1) were used to describe QM/MM van der Waals interactions. The QM region was treated at the hybrid density functional B3LYP/6-31G(d) level of theory, which gives a reasonably good description of the reaction. 12 The enzyme model consisted of 7077 atoms and the solution model contained 7218 atoms. The MM region comprised an approximate 25 Å radius sphere of protein and/or solvent, treated with the CHARMM27 forcefield. 71 The outer 5 Å in each case was fixed (3324 atoms fixed in the enzyme model and 3535 fixed in the solution model),with all other atoms free to move. As there is no evidence for large-scale conformational changes during the reaction, this approach should give a representative sample of reactive conformations in the enzyme. 49,51, 53,54 Each initial structure was fully optimized at the B3LYP/6-31G(d)/CHARMM27 QM/MM level, while restraining the reaction coordinate (r) to -0.5 Å with a harmonic force constant of 500 kcal/mol/Å 2 , to generate starting structures.Reaction pathways were generated by restrained optimizations in both directions along the reaction coordinate, towards the reactant and the product, in steps of 0.2 Å (0.1 Å around the TS), with both the MM and QM systems fully and consistently optimized at each step. Energy profiles were calculated from r = −2.2 Å to 2.2 Å, to identify the reactant and product mini...

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Section: Acs Paragon Plus Environmentmentioning

confidence: 99%

Projector-Based Embedding Eliminates Density Functional Dependence for QM/MM Calculations of Reactions in Enzymes and Solution

Ranaghan

Shchepanovska

Bennie

et al. 2019

J. Chem. Inf. Model.

Self Cite

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“…Remarkably, in vitro analysis suggests that the L718Q T790M double mutant re-sensitizes the receptor to afatinib [93]. Molecular modeling shows that the L718Q mutation appears to block osimertinib from interacting covalently with C797 [94]. Finally, a L747P mutation [95] also renders cells resistant to osimertinib while sensitizing cells to afatinib [96,97].…”

Section: Epidermal Growth Factor Receptor (Egfr)mentioning

confidence: 99%

Secondary Resistant Mutations to Small Molecule Inhibitors in Cancer Cells

Hamid

Petreaca

2020

Cancers

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Secondary resistant mutations in cancer cells arise in response to certain small molecule inhibitors. These mutations inevitably cause recurrence and often progression to a more aggressive form. Resistant mutations may manifest in various forms. For example, some mutations decrease or abrogate the affinity of the drug for the protein. Others restore the function of the enzyme even in the presence of the inhibitor. In some cases, resistance is acquired through activation of a parallel pathway which bypasses the function of the drug targeted pathway. The Catalogue of Somatic Mutations in Cancer (COSMIC) produced a compendium of resistant mutations to small molecule inhibitors reported in the literature. Here, we build on these data and provide a comprehensive review of resistant mutations in cancers. We also discuss mechanistic parallels of resistance.

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“…72,78,79 The statistical error was estimated by averaging the free energy difference between 10-20 ps and 20-30 ps. 80,81 The QM/MM boundary was treated by the pseudo-bond approach 77,82,83 with the improved parameters. 84 All other atoms were described by the same molecular mechanical force eld used in classical MD simulations.…”

Section: Setup For Qm/mm MD Simulationsmentioning

confidence: 99%

Linking inhibitor motions to proteolytic stability of sunflower trypsin inhibitor-1

Wei

Xie

et al. 2019

RSC Adv.

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L718Q mutant EGFR escapes covalent inhibition by stabilizing a non-reactive conformation of the lung cancer drug osimertinib

Abstract: Impact of L718Q mutation on the inhibitory activity of osimertinib on EGFR revealed by free-energy simulations.

Cited by 81 publications

References 55 publications

Projector-Based Embedding Eliminates Density Functional Dependence for QM/MM Calculations of Reactions in Enzymes and Solution

Projector-Based Embedding Eliminates Density Functional Dependence for QM/MM Calculations of Reactions in Enzymes and Solution

Secondary Resistant Mutations to Small Molecule Inhibitors in Cancer Cells

Linking inhibitor motions to proteolytic stability of sunflower trypsin inhibitor-1

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