A miniaturized lead screening platform based on in situ click chemistry and integrated microfluidics

ORGN 658

Jinyi Wang, jywang@mednet.ucla.edu, Crump Institute for Molecular Imaging, Department of Molecular and Medical Pharmacology, University of California, Los Angeles, 700 Westwood Plaza, Los Angeles, CA 90095, Guodong Sui, gsui@mednet.ucla.edu, Crump Institute for Molecular Imaging and Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, 700 Westwood Plaza, Los Angeles, CA 90095, Vani P. Mocharla, vani.mocharla@ctimi.com, Siemens Biomarker Solutions, 6140 Bristol Parkway, Culver City, CA 90230, Hartmuth C. Kolb, Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, and Hsian-Rong Tseng, hrtseng@mednet.ucla.edu, Crump Institute for Molecular Imaging and Department of Molecular and Medical Pharmacology, UCLA, 700 westwood plaza, 1320 crump institute, Los Angeles, CA 90095.
Lead discovery and optimization is one laborious, costly and time-consuming process. Traditionally, it often relies on synthesizing and screening a large compound library to identify few lead molecules. In situ click chemistry is one new approach to synthesis, making use of the target proteins themselves as template to assembly protein inhibitors from reactive building blocks within the confines of the binding sites. In order to reduce the amount of target proteins required in the in situ click chemistry screening and to accelerate this lead screening process, a microfluidic platform with a size of 6cm X 6cm has been developed to perform 64 parallel lead screening reactions at 2.0 microliter (uL) scale. In a proof-of-concept trial, we validate this microfluidics-based in situ click chemistry system with the enzyme, carbonic anhydrase (CA), which has previously been shown to produce high-affinity ligands through 'macroscopic' in situ click chemistry screening. The results indicate that this miniaturized lead screening platform has the advantages of not only providing great precision in metering, but also automated control, chemical/substrate/solvent economy and high throughput.
 

Materials, Devices, and Switches
1:00 PM-5:00 PM, Thursday, 30 March 2006 Georgia World Congress Center -- Georgia Ballroom 2, Oral

Division of Organic Chemistry

The 231st ACS National Meeting, Atlanta, GA, March 26-30, 2006