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      Insight into resistance mechanisms of AZD4547 and E3810 to FGFR1 gatekeeper mutation via theoretical study

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          Inhibitors targeting the amplification of the fibroblast growth factor receptor 1 (FGFR1) have found success in the treatment of FGFR1-positive squamous cell lung and breast cancers. A secondary mutation of gatekeeper residue (V561M) in the binding site has been linked to the acquired resistance. Recently, two well-known small molecule inhibitors of FGFR1, AZD4547 and E3810, reported that the V561M mutation confers significant resistance to E3810, while retaining affinity for AZD4547. FGFR1 is widely investigated as potential therapeutic target, while there are few computational studies made to understand the resistance mechanisms about FGFR1 V561M gatekeeper mutation. In this study, molecular docking, classical molecular dynamics simulations, molecular mechanics/generalized born surface area (MM/GBSA) free energy calculations, and umbrella sampling (US) simulations were carried out to make clear the principle of the binding preference of AZD4547 and E3810 toward FGFR1 V561M gatekeeper mutation. The results provided by MM/GBSA reveal that AZD4547 has similar binding affinity to both FGFR1 WT and FGFR1 V561M, whereas E3810 has much higher binding affinity to FGFR1 WT than to FGFR1 V561M. Comparison of individual energy terms indicates that the major variation of E3810 between FGFR1 WT and FGFR1 V561M are van der Waals interactions. In addition, US simulations prove that the potential of mean force (PMF) profile of AZD4547 toward FGFR1 WT and FGFR1 V561M has similar PMF depth. However, the PMF profile of E3810 toward FGFR1 WT and FGFR1 V561M has much higher PMF depth, suggesting that E3810 is more easily dissociated from FGFR1 V561M than from FGFR1 WT. The results not only show the drug-resistance determinants of FGFR1 gatekeeper mutation but also provide valuable implications and provide vital clues for the development of new inhibitors to combat drug resistance.

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          Most cited references 28

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          MMPBSA.py: An Efficient Program for End-State Free Energy Calculations.

          MM-PBSA is a post-processing end-state method to calculate free energies of molecules in solution. MMPBSA.py is a program written in Python for streamlining end-state free energy calculations using ensembles derived from molecular dynamics (MD) or Monte Carlo (MC) simulations. Several implicit solvation models are available with MMPBSA.py, including the Poisson-Boltzmann Model, the Generalized Born Model, and the Reference Interaction Site Model. Vibrational frequencies may be calculated using normal mode or quasi-harmonic analysis to approximate the solute entropy. Specific interactions can also be dissected using free energy decomposition or alanine scanning. A parallel implementation significantly speeds up the calculation by dividing frames evenly across available processors. MMPBSA.py is an efficient, user-friendly program with the flexibility to accommodate the needs of users performing end-state free energy calculations. The source code can be downloaded at http://ambermd.org/ with AmberTools, released under the GNU General Public License.
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            The dynamic process of β(2)-adrenergic receptor activation.

            G-protein-coupled receptors (GPCRs) can modulate diverse signaling pathways, often in a ligand-specific manner. The full range of functionally relevant GPCR conformations is poorly understood. Here, we use NMR spectroscopy to characterize the conformational dynamics of the transmembrane core of the β(2)-adrenergic receptor (β(2)AR), a prototypical GPCR. We labeled β(2)AR with (13)CH(3)ε-methionine and obtained HSQC spectra of unliganded receptor as well as receptor bound to an inverse agonist, an agonist, and a G-protein-mimetic nanobody. These studies provide evidence for conformational states not observed in crystal structures, as well as substantial conformational heterogeneity in agonist- and inverse-agonist-bound preparations. They also show that for β(2)AR, unlike rhodopsin, an agonist alone does not stabilize a fully active conformation, suggesting that the conformational link between the agonist-binding pocket and the G-protein-coupling surface is not rigid. The observed heterogeneity may be important for β(2)AR's ability to engage multiple signaling and regulatory proteins. Copyright © 2013 Elsevier Inc. All rights reserved.
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              Crystal structure of a ternary FGF-FGFR-heparin complex reveals a dual role for heparin in FGFR binding and dimerization.

              The crystal structure of a dimeric 2:2:2 FGF:FGFR:heparin ternary complex at 3 A resolution has been determined. Within each 1:1 FGF:FGFR complex, heparin makes numerous contacts with both FGF and FGFR, thereby augmenting FGF-FGFR binding. Heparin also interacts with FGFR in the adjoining 1:1 FGF:FGFR complex to promote FGFR dimerization. The 6-O-sulfate group of heparin plays a pivotal role in mediating both interactions. The unexpected stoichiometry of heparin binding in the structure led us to propose a revised model for FGFR dimerization. Biochemical data in support of this model are also presented. This model provides a structural basis for FGFR activation by small molecule heparin analogs and may facilitate the design of heparin mimetics capable of modulating FGF signaling.

                Author and article information

                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                17 February 2017
                : 11
                : 451-461
                [1 ]Pharmacy Department, Jining First People’s Hospital
                [2 ]Department of Obstetrics, Affiliated Hospital of Jining Medical University, Jining, Shandong
                [3 ]Department of Rheumatology, The First Affiliated Hospital of Wenzhou Medical University
                [4 ]School of Pharmacy, Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China
                Author notes
                Correspondence: Ting Zhang, Department of Rheumatology, The First Affiliated Hospital of Wenzhou Medical University, Shangcai, Nanbaixiang, Ouhai, Wenzhou 325000, People’s Republic of China, Tel/fax +86 577 5557 9263, Email ting_zhang06@ 123456sina.com

                These authors contributed equally to this work

                © 2017 Liang et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

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