HIGH THROUGHPUT FRAGMENT BASED DRUG DISCOVERY BY SPR IMAGING OF CHEMICAL MICROARRAYS
NovAlix Pharma, Im Neuenheimer Feld 518, 69120 Heidelberg, Germany
Surface Plasmon Resonance (SPR) has become a very popular tool for fragment based screening. Traditional channel based instruments typically exhibit a medium throughput, useful for secondary hit confirmation of a limited number of compounds. For truly primary screening of large fragment libraries, however, SPR array technology is ideal as it attains a high throughput of >36,000 interactions per day and per SPR instrument with a sensitivity high enough to pick up even very weak fragment-protein interactions.
In more common SPR based screening approaches the protein needs to be immobilized on the sensor surface, which often introduces artifacts due to instabilities of the protein on the surface or insufficient solubility of the (fragment) analyte. The Graffinity “reverse” SPR detection scheme avoids such problems by linking a large, unique and diverse collection of screening compounds (>116k compounds including >25k fragments with MW< 300Da) to gold chips with 9,216 sensor fields/array. Such chemical microarrays can be rapidly screened against any kind of soluble target in a label-free manner using in-house developed SPR imaging instruments.
Case studies (from over 100 successfully screened proteins) will demonstrate the versatility of the approach in combination with complementary hit confirmation tools such as biochemical assays, Xray or ESI-MS.