Margot Beukers | Medicinal Chemistry

Universiteit Leiden

Margot Beukers, Ph.D.

Position:

Project manager Top Institute Pharma GPCR forum project

Telephone number: +31 (0)71 527 4607
E-mail address: beukers@chem.leidenuniv.nl
Faculty/Unit: Faculty of Science, Leiden/Amsterdam Center for Drug Research, Medicinal Chemistry
Office address: Gorlaeus Laboratories
Einsteinweg 55
2333 CC Leiden
roomnumber L-073

Biography

Receptor-ligand interactions have been my prime interest since 1989 when I graduated from Leiden University at the Center for Bio-Pharmaceutical Sciences. Hence I enjoyed my research on insulin-like growth factor receptors with Prof R.G. Rosenfeld at Stanford University in the USA. Subsequently, I studied the degradation of extracellular adenosine and adenine nucleotides at the division of Medicinal Chemistry of the Leiden/Amsterdam Center for Drug Research at Leiden University. After defending my thesis in 1995 I moved on to G protein-coupled receptors (GPCRs).

The majority of the drugs that are on the market today do interact with these proteins. Despite this interest and many efforts very little is known about the three-dimensional structure of these proteins. To obtain structural information sufficient quantities of pure protein are required. Insect cells have proved to be useful to express functional rhodopsin in high quantities. During a post-doc at the Free University of Amsterdam in collaboration with Nijmegen University I was able to express Histamine H₂ receptors in these insect cells. Next I spend much time and effort on the creation of a database on GPCRs. This EU-sponsored project was and still is very successful (http://www.gpcr.org/7tm). In addition, a sub database on GPCR mutations (Tromsø, Norway) was included and expanded and is available from this same link.

To study receptor-ligand interactions of GPCRs I have employed a wide range of techniques varying from molecular biology to biophysical techniques. In addition, I am involved in the set-up of a facility for the production of membrane proteins, mainly GPCRs. The ultimate aim is to obtain structural information on the function of these proteins at the amino acid level.

The focus throughout my career has been on multidisciplinary collaborative projects. As of 2007 I am full time employed as a project manager on two pre-competitive research public-private partnership projects in which industrial and academic partners collaborate. Both projects have been granted by the Dutch Top Institute Pharma. In the mechanism-based PK-PD modeling platform 4 academic and 6 industrial partners join forces. The second project is the GPCR forum in which 5 academic and 2 industrial partners have teamed up to address novel concepts in the fields of receptor activation, dimerization, bioinformatics and cheminformatics.

2010

van der Horst, E., Peironcely, J., IJzerman, A., Beukers, M., Lane, J., van Vlijmen, H., Emmerich, M., Okuno, Y., Bender, A. , A novel chemogenomics analysis of G protein-coupled receptors (GPCRs) and their ligands: a potential strategy for receptor de-orphanization, BMC Bioinformatics, vol. 11, no. 1, pp. 316.

2009

Lane, J.R., Beukers, M.W., Mulder-Krieger, T., Ijzerman, A.P. , The endocannabinoid 2-arachidonylglycerol is a negative allosteric modulator of the human A3 adenosine receptor, Biochemical Pharmacology, vol. In Press, .

2008

Mantri, M., de Graaf, O., van Veldhoven, J., Göblyös, A., von Frijtag Drabbe Künzel, J.K., Mulder-Krieger, T., Link, R., de Vries, H., Beukers, M.W., Brussee, J., IJzerman, A.P. , 2-Amino-6-furan-2-yl-4-substituted Nicotinonitriles as A2A Adenosine Receptor Antagonists, Journal of Medicinal Chemistry, vol. 51, no. 15, pp. 4449-4455.

van Veldhoven, J.P.D., Chang, L.C.W., von Frijtag Drabbe Künzel, J.K., Mulder-Krieger, T., Struensee-Link, R., Beukers, M.W., Brussee, J., IJzerman, A.P. , A new generation of adenosine receptor antagonists: from di- to trisubstituted aminopyrimidines, Bioorganic & Medicinal Chemistry, vol. 16, no. 6, pp. 2741-52.

Klaasse, E.C., IJzerman, A.P., de Grip, W.J., Beukers, M.W. , Internalization and desensitization of adenosine receptors, Purinergic Signalling, vol. 4, no. 1, pp. 21-37.

2007

Li, Q., Ye, K., Blad, C.C., den Dulk, H., Brouwer, J., IJzerman, A.P., Beukers, M.W. , ZM241385, DPCPX, MRS1706 are inverse agonists with different relative intrinsic efficacies on constitutively active mutants of the human adenosine A2B receptor, The Journal of Pharmacology and Experimental Therapeutics, vol. 320, no. 2, pp. 637-45.

2006

Ye, K., Lameijer, E.M., Beukers, M.W., IJzerman, A.P. , A two-entropies analysis to identify functional positions in the transmembrane region of class A G protein-coupled receptors, Proteins: Structure, Function, and Bioinformatics, vol. 63, no. 4, pp. 1018-1030.

Beukers, M.W., Meurs, I., IJzerman, A.P. , Structure-affinity relationships of adenosine A2B receptor ligands, Medicinal Research Reviews, vol. 26, no. 5, pp. 667-98.

2005

Chang, L.C.W., von Frijtag Drabbe Künzel, J.K., Mulder-Krieger, T., Spanjersberg, R.F., Roerink, S.F., van den Hout, G., Beukers, M.W., Brussee, J., IJzerman, A.P. , A series of ligands displaying a remarkable agonistic-antagonistic profile at the adenosine A1 receptor, Journal of Medicinal Chemistry, vol. 48, no. 6, pp. 2045-53.

Klaasse, E.C., van den Hout, G., Roerink, S.F., de Grip, W.J., IJzerman, A.P., Beukers, M.W. , Allosteric modulators affect the internalization of human adenosine A1 receptors, European Journal of Pharmacology, vol. 522, no. 1-3, pp. 1-8.

Beukers, M.W., IJzerman, A.P. , Techniques: how to boost GPCR mutagenesis studies using yeast, Trends in Pharmacological Sciences, vol. 26, no. 10, pp. 533-9.

2004

Beukers, M.W., Chang, L.C.W., von Frijtag Drabbe Künzel, J.K., Mulder-Krieger, T., Spanjersberg, R.F., Brussee, J., IJzerman, A.P. , New, non-adenosine, high-potency agonists for the human adenosine A2B receptor with an improved selectivity profile compared to the reference agonist N-ethylcarboxamidoadenosine, Journal of Medicinal Chemistry, vol. 47, no. 15, pp. 3707-9.

Beukers, M.W., van Oppenraaij, J., van der Hoorn, P.P.W., Blad, C.C., den Dulk, H., Brouwer, J., IJzerman, A.P. , Random mutagenesis of the human adenosine A2B receptor followed by growth selection in yeast. Identification of constitutively active and gain of function mutations, Molecular Pharmacology, vol. 65, no. 3, pp. 702-10.

Chang, L.C.W., Spanjersberg, R.F., von Frijtag Drabbe Künzel, J.K., Mulder-Krieger, T., van den Hout, G., Beukers, M.W., Brussee, J., IJzerman, A.P. , 2,4,6-Trisubstituted Pyrimidines as a New Class of Selective Adenosine A1 Receptor Antagonists, Journal of Medicinal Chemistry, vol. 47, no. 26, pp. 6529-6540.

2003

Beukers, M.W., Wanner, M.J., Von Frijtag Drabbe Künzel, J.K., Klaasse, E.C., IJzerman, A.P., Koomen, G. , N6-cyclopentyl-2-(3-phenylaminocarbonyltriazene-1-yl)adenosine (TCPA), a very selective agonist with high affinity for the human adenosine A1 receptor, Journal of Medicinal Chemistry, vol. 46, no. 8, pp. 1492-503.

Samsonova, E.V., Bäck, T., Beukers, M.W., IJzerman, A.P., Kok, J.N. , Combining and comparing cluster methods in a receptor database, ADVANCES IN INTELLIGENT DATA ANALYSIS V, vol. 2810, pp. 341-351.

2002

Lorenzen, A., Beukers, M.W., van der Graaf, P.H., Lang, H., van Muijlwijk-Koezen, J., de Groote, M., Menge, W., Schwabe, U., IJzerman, A.P. , Modulation of agonist responses at the A(1) adenosine receptor by an irreversible antagonist, receptor-G protein uncoupling and by the G protein activation state, Biochemical Pharmacology, vol. 64, no. 8, pp. 1251-65.

Edvardsen, O., Reiersen, A.L., Beukers, M.W., Kristiansen, K. , tGRAP, the G-protein coupled receptors mutant database, Nucleic Acids Research, vol. 30, no. 1, pp. 361-3.

15/08/2009

Medicinal Chemistry