Computational drug design

Docked ligand Pharmacophore

Left) Docking of a ligand into the binding site of a receptor target structure provides a model of the mode-of-action, guiding further medicinal chemistry optimisation and pharmacological validation by mutagenesis. Right) Pharmacophore elements are placed based on known ligands to give a 3D representation of the features important for target interaction and activity, and are used to identified new ligands with other chemical structures. 

"Today the computer is just as important a tool for chemists as the test tube. Simulations are so realistic that they predict the outcome of traditional experiments.

Finale of the motivation for the

2013 Nobel Prize in Chemistry

Today, computational models are integral for the rationalization of experimental data and generation of hypotheses for new studies. In the Gloriam group, we combine bioinformatics, chemoinformatics and computational chemistry in computational drug design at GPCRs. We also develop new methods for virtual screening, chemogenomics and design of target-directed focused screening libraries.

The work has led to the identification of novel ligands for the chemokine, glutamate, histamine and serotonin receptors. It is highly interdisciplinary, building on collaborations with the Chemistry and Medicinal Chemistry and Molecular Pharmacology groups at the Department of Drug Design and Pharmacology, as well as several international labs.

Selected Publications

Identification of new tool compounds
Harpsøe K, Isberg V, Tehan BG, Weiss D, Arsova A, Marshall FH, Bräuner-Osborne H, Gloriam DE.
Selective Negative Allosteric Modulation Of Metabotropic Glutamate Receptors - A Structural Perspective of Ligands and Mutants.
Sci Rep (IF 5.6). 2015 Sep 11;5:13869.

Chalikiopoulos A, Thiele S, Malmgaard-Clausen M, Rydberg P, Isberg V, Ulven T, Frimurer T, Rosenkilde M, Gloriam DE
Structure-activity relationships and identification of optimized CC-chemokine receptor CCR1, 5 and 8 metal-ion chelators
J Chem Inf Model. 2013 Nov 25;53(11):2863-73.; PMID: 24083637

Jensen AA, Plath N, Pedersen MH, Isberg V, Krall J, Wellendorph P, Stensbøl TB, Gloriam DE, Krogsgaard-Larsen P, Frølund B
Design, synthesis, and pharmacological characterization of N- and O-substituted 5,6,7,8-tetrahydro-4H-isoxazolo[4,5-d]azepin-3-ol analogues: novel 5-HT(2A)/5-HT(2C) receptor agonists with pro-cognitive properties
J Med Chem. 2013 Feb 14;56(3):1211-27; PMID: 23301527

Thiele S, Malmgaard-Clausen M, Engel-Andreasen J, Steen A, Rummel PC, Nielsen MC, Gloriam DE, Frimurer TM, Ulven T, Rosenkilde MM
Modulation in selectivity and allosteric properties of small-molecule ligands for CC-chemokine receptors
J Med Chem. 2012 Sep 27;55(18):8164-77; PMID: 22957890

Mølck C, Harpsøe K, Gloriam DE, Clausen RP, Madsen U, Pedersen LO, Jimenez HN, Nielsen SM, Mathiesen JM, Brauner-Osborne H
Pharmacological Characterization and Modeling of the Binding Sites of Novel 1,3-bis(pyridinylethynyl)benzenes as Metabotropic Glutamate Receptor 5-selective Negative Allosteric Modulators
Mol Pharmacol. 2012 Nov;82(5):929-37; PMID: 22899869

New computational methods
Fidom K, Isberg V, Hauser AS, Mordalski S, Lehto T, Bojarski AJ, Gloriam DE.
A new crystal structure fragment-based pharmacophore method for G protein-coupled receptors.
Methods. 2014 Oct 5. pii: S1046-2023(14)00315-6.; PMID: 25286328

Receptor structure modelling
Kufareva I, Katritch V, Gloriam DE, other GPCR Dock participants, Stevens RC, Abagyan R
Advances in GPCR modeling evaluated by the GPCR Dock 2013 assessment: meeting new challenges
Structure. 2014 Aug 5;22(8):1120-39.; PMID: 25066135

Ísberg V, Balle T, Sander T, Jørgensen FS, Gloriam DE
G Protein- and Agonist-Bound Serotonin 5-HT(2A) Receptor Model Activated by Steered Molecular Dynamics Simulations
J Chem Inf Model. 2011 Feb 28;51(2):315-25; PMID: 21261291

Structure-activity relationships modelling
Isberg V, Paine J, Leth-Petersen S, Kristensen J, Gloriam DE
Structure-Activity Relationships of Constrained Phenylethylamine Ligands for the Serotonin 5-HT2 Receptors
PLoS One. 2013 Nov 7;8(11):e78515.; PMID: 24244317

Kaae BH, Harpsøe K, Kvist T, Mathiesen JM, Mølck C, Gloriam D, Jimenez HN, Uberti MA, Nielsen SM, Nielsen B, Bräuner-Osborne H, Sauerberg P, Clausen RP, Madsen U
Structure-Activity Relationships for Negative Allosteric mGluR5 Modulators
ChemMedChem. 2012 Mar 5;7(3):440-51; PMID: 22267204