Cell Systems and Drug Safety
Allosterism
The recognition that there may be more, so-called allosteric binding sites on a given receptor has also fueled our synthetic efforts. Over the last few years we have focused on many drug targets (adenosine A1, A2A and A3 receptors, the mGlu2 receptor and a classic ‘anti-target’, the hERG channel) to explore this notion.
We have identified and designed new compounds that enhance the action of a classic agonist (a so-called positive allosteric modulator – PAM) or, very differently, act as a new class of antagonists (negative allosteric modulators – NAMs). As a PAM for the adenosine for the hERG channel (exemplified by LUF 7346) may even reverse the cardiotoxicity induced by hERG somatic mutations, and save the life of patients suffering from this genetic malfunctioning.
Such compounds would be fantastic representatives of true ‘precision medicine’. Structural evidence for compounds allosterically influencing each other came from our joint work with Tracy Handel’s team at San Diego’s School of Pharmacy, with whom we solved the structure of the chemokine CCR2 receptor bound to two small molecules at the same time. From pharmacological experiments we had already learned that the two molecules, BMS-681 and CCR2-RA-[R], reinforced their binding to the receptor.
Related publications
- Doornbos M.L.J., Cid J.M., Haubrich J., Nunes A., van de Sande J.W., Vermond S.C., Mulder-Krieger T., Trabanco A.A., Ahnaou A., Drinkenburg W.H., Lavreysen H., Heitman L.H., IJzerman A.P., Tresadern G., Discovery and Kinetic Profiling of 7-Aryl-1,2,4-triazolo[4,3-a]pyridines: Positive Allosteric Modulators of the Metabotropic Glutamate Receptor 2. J Med Chem 2017, 60(15):6704-6720.
- Zheng Y., Qin L., Zacarías N.V., de Vries H., Han G.W., Gustavsson M., Dabros M., Zhao C., Cherney R.J., Carter P., Stamos D., Abagyan R., Cherezov V., Stevens R.C., IJzerman A.P., Heitman L.H., Tebben A., Kufareva I., Handel T.M., Structure of CC chemokine receptor 2 with orthosteric and allosteric antagonists. Nature 2016, 540(7633):458-461.
- Sala L., Yu Z., Ward-van Oostwaard D., van Veldhoven J.P., Moretti A., Laugwitz K.L., Mummery C.L., IJzerman A.P., Bellin M., A new hERG allosteric modulator rescues genetic and drug-induced long-QT syndrome phenotypes in cardiomyocytes from isogenic pairs of patient induced pluripotent stem cells. EMBO Mol Med 2016, 8(9):1065-81.
- Massink A., Louvel J., Adlere I., van Veen C., Huisman B.J., Dijksteel G.S., Guo D., Lenselink E.B., Buckley B.J., Matthews H., Ranson M., Kelso M., IJzerman A.P., 5'-Substituted Amiloride Derivatives as Allosteric Modulators Binding in the Sodium Ion Pocket of the Adenosine A2A Receptor. J Med Chem 2016, 59(10):4769-77.
- Massink A., Gutiérrez-de-Terán H., Lenselink E.B., Ortiz Zacarías N.V., Xia L., Heitman L.H., Katritch V., Stevens R.C., IJzerman A.P., Sodium ion binding pocket mutations and adenosine A2A receptor function. Mol Pharmacol 2015, 87(2):305-13.
- Gutiérrez-de-Terán H., Massink A., Rodríguez D., Liu W., Han G.W., Joseph J.S., Katritch I., Heitman L.H., Xia L., IJzerman A.P., Cherezov V., Katritch V., Stevens R.C., The role of a sodium ion binding site in the allosteric modulation of the A(2A) adenosine G protein-coupled receptor. Structure 2013, 21(12):2175-85.
- Liu W., Chun E., Thompson A.A., Chubukov P., Xu F., Katritch V., Han G.W., Roth C.B., Heitman L.H., IJzerman A.P., Cherezov V., Stevens R.C., Structural basis for allosteric regulation of GPCRs by sodium ions. Science 2012, 337(6091):232-6.