Tommy Sander

Curriculum vitae (PDF version)

Publication list

Within the field of medicinal chemistry, my research focuses on computational chemistry and molecular modeling, where various computational techniques are employed to describe (interactions between) ligands and receptors. I have worked with GPCR receptors (α₁ and 5-HT_2A) and ligand-gated ion channels (iGluR2 and GABA_A), and my experience with computational tools include normal mode analysis, molecular dynamics, docking, QM calculations, and pharmacophore, QSAR and homology modeling.

Only limited structural knowledge of the Cys-loop receptors exists, namely the 4Å resolution electron microscopy of a nAChR from an electric ray (1) and the recently published crystal structure of the ligand binding domain of the mouse nAChR α₁ subunit (2). However, the ACh binding protein (AChBP) isolated from snails, which resembles the pentameric structure of the ligand binding domain of Cys-loop receptors, has been crystallized with various nAChR ligands and toxins, and detailed X-ray structures hereof have been published (e.g. refs. 3-6).

The project

Based on primarily the AChBP structures, I will build homology models of the most common GABA_A receptor subtype(s), and using the computational techniques Normal Mode Analysis (NMA) and Molecular Dynamics (MD) the flexibility of these will be modeled. The receptor models will be used in collaboration with the medicinal chemistry group (Bente Frølund and Mogens Nielsen) to design new GABA_A ligands to be synthesized and tested, and with the molecular pharmacology group (Anders A. Jensen and Marianne L. Bergmann) to understand and make suggestions to new mutational studies.

In addition, a stay at the University of California, San Diego, in the group of professor J. Andrew McCammon has been completed during the period August 2008 through January 2009. During this stay a variety of MD techniques were tested, and simulations with and without ligands were performed. Also, advanced methods were employed to analyse the trajectories, including PCA, essential dynamics, clustering and other types.

1. Unwin, N. Refined structure of the nicotinic acetylcholine receptor at 4Å resolution. J Mol Biol 2005, 346, 967-989.
2. Dellisanti, C.D.; Yao, Y.; Stroud, J.C.; Wang, Z.Z.; Chen, L. Crystal structure of the extracellular domain of nAChR alpha1 bound to alpha-bungarotoxin at 1.94 A resolution. Nat Neurosci 2007, 10, 953-962.
3. Smit, A.B. et al. A glia-derived acetylcholine-binding protein that modulates synaptic transmission. Nature 2001, 411, 261-268.
4. Brejc, K. et al. Crystal structure of an ACh-binding protein reveals the ligand-binding domain of nicotinic receptors. Nature 2001, 411, 269-276.
5. Celie, P.H.; van Rossum-Fikkert, S.E.; van Dijk, W.J.; Brejc, K.; Smit, A.B.; Sixma, T.K. Nicotine and carbamylcholine binding to nicotinic acetylcholine receptors as studied in AChBP crystal structures. Neuron 2004, 41, 907-914.
6. Hansen, S.B.; Sulzenbacher, G.; Huxford, T.; Marchot, P.; Taylor, P.; Bourne, Y. Structures of Aplysia AChBP complexes with nicotinic agonists and antagonists reveal distinctive binding interfaces and conformations. EMBO J 2005, 24, 3635-3646.

Main supervisor
Bente Frølund (associate professor, Pharma, KU)
(Tommy Liljefors was main supervisor until his retirement 1^st September 2007)

Co-supervisors
Thomas Balle (associate professor, Pharma, KU)
Anne Techau Jørgensen (Computational chemist, H. Lundbeck A/S)

On January 7, 2011, I defended my PhD thesis with the following persons as the assessment committee:

• Cynthia Czajkowski, Professor, PhD, University of Madison – Wisconsin
• Birgit Schiøtt, Professor, PhD, Aarhus Universitet
• Lars Olsen, Associate Professor, PhD, University of Copenhagen