1 http://www.beilstein-institut.de/bozen2004/proceedings/Bleicher/Bleicher.pdf The Chemical Theatre of Biological Systems, May 24 th - 28 th , 2004, Bozen, Italy GPCR HIT DISCOVERY BEYOND HTS KONRAD H. BLEICHER *,1 , ALEXANDER I. ALANINE 1 , MARK ROGER-EVANS 1 AND GISBERT SCHNEIDER 2 1 F. Hoffmann-La Roche AG, Pharmaceuticals Devision, CH 4070 Basel, Switzerland 2 Johann Wolfgang Goethe University Frankfurt, Marie-Curie-Str. 11, D-60439 Frankfurt, Germany E-Mail: *konrad.bleicher@roche.com Received: 20 th September 2004 / Published: 22 nd July 2005 ABSTRACT High-throughput screening is meanwhile well established in most pharmaceutical companies. Although it is routinely applied for most biological targets, several limitations ask for alternative methodologies. This article will describe two different approaches where highly potent ligands for G-protein coupled receptor targets were identified without the application of random high-throughput screening. INTRODUCTION A recent analysis of the targets where drugs have been successfully developed shows that about 45% of these targets belong to receptors of which most are G-protein coupled (GPCRs)[1]. Such proteins are involved in various disease pathways and are recognized as highly valuable targets for most therapeutic indications [2,3]. Besides the obvious commercial aspects, the large number of launched drugs for G-protein coupled receptors also gives confidence in the 'drugability' of such seven transmembrane proteins. Due to their size and high lipophilicity the isolation and crystallization of GPCRs turned out to be extremely difficult, making a structure based drug design approach currently unrealistic. Therefore GPCR programmes are usually initiated after a successful high-throughput screening campaign (HTS) has been accomplished.