Bukrinski, Jens T.

Frederiksen, Tine Maja

Harris, Pernille

Peters, Günther H.J.

Online Research Database In Technology

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Downloaded from orbit.dtu.dk on: Nov 08, 2017Interactions of a Glucagon-like peptide 1 and a Glucagon-like peptide 1 analogue,liraglutide, with the endogenous receptorFrederiksen, Tine Maja; Harris, Pernille; Bukrinski, Jens T.; Peters, Günther H.J.Publication date:2015Document VersionPublisher's PDF, also known as Version of recordLink back to DTU OrbitCitation (APA):Frederiksen, T. M., Harris, P., Bukrinski, J. T., & Peters, G. H. J. (2015). Interactions of a Glucagon-like peptide1 and a Glucagon-like peptide 1 analogue, liraglutide, with the endogenous receptor. Abstract from Annualmeeting of the Swedish Chemical Society 'Theoretical Chemistry Section 2015', Kalmar, Sweden.Drug Design and Biomedical Research10 Interactions of a Glucagon-like peptide 1 and a Glucagon-like peptide 1 analogue, liraglutide, with the endogenous re-ceptorTine M. Frederiksen*; Pernille Harris*; Jens T. Bukrinski’; Gu¨nther H. Peters*.*Technical University of Denmark, Department of Chemistry, Kemitorvet 207, DK-2800 Kgs. Lyngby, Denmark;’Novozymes A/S, Krogshøjvej 36, Bagsværd, DK-2880, DenmarkWe have investigated the interactions of the Glucagon-like peptide 1 (GLP-1) and a GLP1 analogue,liraglutide, with the endogenous receptor using molecular dynamics (MD) simulations. It is evident thatthe attached fatty acid (FA) chain in liraglutide enhances the affinity for the GLP-1 receptor since li-raglutide binds approximately 10 times stronger to the receptor than GLP-1 [1,2]. Our hypothesis isthat the FA chain will interact with the hydrophobic pocket of the extracellular domain (ECD) and thusstrengthen the interactions between the peptide and the receptor compared to GLP-1. Furthermore, theshape of the ligand is of importance to the affinity as more interactions can be obtained if the ligandis shaped so that its N-terminal can interact with the top of the transmembrane (TM) region. To shedlight on these differences, simulations were performed on fully hydrated receptor-ligand complexes ina 1-palmitoyl-2-oleoylphosphatidylcholine membrane. The receptor structure was built from the exper-imentally determined ECD structure (PDB entry 3IOL; [3]) and a homology model structure of the 7alpha helix TM region using the class B human glucagon G protein coupled receptor structure (4L6R; [4]).To address the importance on the shape of the peptide, both the GLP-1 and the liraglutide complexesare built in two conformations; one where the ligands are simulated in the L-shape as seen in the crystalstructure 1JRJ and described by Thornton and Gorenstein [5], and one where they are in a straight formas seen in the crystal structures 4APD and 3IOL. Preliminary results show that the complex maintainsits overall structure. Slight rearrangements are observed in the TM region, where it turns slightly aroundits own axis to adjust to the surrounding phospholipids. The same applies for the secondary structure inECD, which is preserved throughout the simulations. A displacement is observed where ECD moves awayfrom the TM region which results in an extension of the GLP-1 N-terminal and the coil region aroundthe middle kink. This movement occurs on a relatively short time scale, and it happens within the first20 ns. This is most likely in response to the adaption of the TM region to the lipid environment. Thestability is, however, maintained since the overall secondary structure of both ECD and the peptide ispreserved through this extension. Although an extension of the peptide occurs, the interactions reportedbetween GLP-1 and ECD are withheld throughout the simulations. Further analyses are in progress andshould be able to identify the key interactions that determine the difference in binding affinity of GLP-1and liraglutide towards the endogenous receptor.[1] Thorkildsen, C. et al., 2003, JPET 307:490-496. [2] Secher, A. et al., 2014, J. Clin. Invest. 124(10):4473-4488. [3] Underwood, C. R. et al., 2010, J. Biol. Chem., 285:723-730. [4] Siu, F. Y. et al., 2013, Nature499:444-449. [5] Thornton, K. & Gorenstein, D.G. Biochemistry 1994, 33:3532-3539.11 Discovery of CREBBP bromodomain ligands by high-throughputdocking and hit optimization guided by molecular dynamicsMin Xu, Andrea Unzue, Jing Dong, Lars Wiedmer, Dimitrios Spiliotopoulos, CristinaNevado, and Amedeo CaflischWe have identified two chemotypes of CREBBP bromodomain ligands by fragment-based high-throughputdocking with a hit rate of 12%. Guided by the docked pose and molecular dynamics simulations, oneof the two hits was improved by medicinal chemistry into a low nanomolar lead with very good ligandefficiency and selectivity as measured by isothermal titration calorimetry. The crystal structures of ananomolar derivative has validated the pose of the hit obtained in silico. Some of the derivatives inhibitproliferation of a small subset of leukemia cell lines.6

Interactions of a Glucagon-like peptide 1 and a Glucagon-like peptide 1 analogue, liraglutide, with the endogenous receptor

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Interactions of a Glucagon-like peptide 1 and a Glucagon-like peptide 1 analogue, liraglutide, with the endogenous receptor

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