Computational Study on the Effect of Inactivating/Activating Mutations on the Inhibition of MEK1 by Trametinib

Abstract

Activation of the mitogen-activated protein kinase (MAPK) signaling pathway regulated by human MAP kinase 1 (MEK1) is associated with the carcinogenesis and progression of numerous cancers. In addition, two active mutations (P124S and E203K) have been reported to enhance the activity of MEK1, thereby eventually leading to the tumorigenesis of cancer. Trametinib is an MEK1 inhibitor for treating EML4-ALK-positive, EGFR-activated, and KRAS-mutant lung cancers. Therefore, in this study, molecular docking and molecular dynamic (MD) simulations were performed to explore the effects of inactive/active mutations (A52V/P124S and E203K) on the conformational changes of MEK1 and the changes in the interaction of MEK1 with trametinib. Moreover, steered molecular dynamic (SMD) simulations were further utilized to compare the dissociation processes of trametinib from the wild-type (WT) MEK1 and two active mutants (P124S and E203K). As a result, trametinib had stronger interactions with the non-active MEK1 (WT and A52V mutant) than the two active mutants (P124S and E203K). Moreover, two active mutants may make the allosteric channel of MEK1 wider and shorter than that of the non-active types (WT and A52V mutant). Hence, trametinib could dissociate from the active mutants (P124S and E203K) more easily compared with the WT MEK1. In summary, our theoretical results demonstrated that the active mutations may attenuate the inhibitory effects of MEK inhibitor (trametinib) on MEK1, which could be crucial clues for future anti-cancer treatment.

Investigating the Retained Inhibitory Effect of Cobimetinib against p.P124L Mutated MEK1: A Combined Liquid Biopsy and in Silico Approach

“…The sequencing of the ctDNA identified the presence, beyond the BRAF p.V600E, of the MEK1 p.P124L mutation and also of the BRAF gain at the progression, conditions that are responsible for the rapid establishment of resistance to the first-line therapy. Since previous studies demonstrated that the MEK1 mutations at codon 124 are able to decrease the interaction between MEK1 and trametinib and/or selumetinib [ 39 , 40 ], we searched for an alternative inhibitor compatible with the presence of this mutation. By molecular dynamics simulation, cobimetinib was predicted to fit the MEK1 binding site, despite the presence of the p.P124L mutation ( Figure 1 ).…”

Molecular and Pathological Profiling of Corresponding Treatment-Naïve and Neoadjuvant Pazopanib-Treated High-Risk Soft Tissue Sarcoma Samples of the GISG-04/NOPASS Study

“…This mutation has been characterized as constitutively active and achieved high levels of phosphorylated ERK within cell line experiments [24]. However, recent molecular docking and molecular dynamic simulations showed that MAP2K1 E203K may attenuate the inhibitory effects of trametinib on MEK1, making a clinical benefit in this context unlikely [25]. Thus far, there is no evidence to show if the effect of other MEK inhibitors would be equally attenuated by the mutation.…”

Molecular Dockings and Molecular Dynamics Simulations Reveal the Potency of Different Inhibitors against Xanthine Oxidase

“…MD trajectories can be visualized in the visual molecular dynamics (VMD) 1.9.1 software. The structural parameters of the four systems were accessed through the root-mean-square-deviation (RMSD), all-to-all RMSD, root-mean square-fluctuation (RMSF), radius of gyration (R g ), and solvent accessible surface area (SASA) analyses. , …”