Discovery of novel active site-directed pharmacological chaperones to increase the cellular activity of Gaucher disease associated glucocerebrosidase variants guided by virtual screening

MEDI 472

Tingwei Mu, tingwei@scripps.edu1, Yunfeng Hu, yunfeng@scripps.edu2, Arthur J. Olson, olson@scripps.edu2, and Jeffery W. Kelly, jkelly@scripps.edu1. (1) Department of Chemistry, The Scripps Research Institute, 10550 N Torrey Pines Rd, BCC265, La Joll, CA 92037, (2) Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, MB5, La Jolla, CA 92037
Gaucher disease is the most prevalent lysosome storage disorder resulting from deficient lysosomal glucocerebrosidase (GC) activity. Clinically important GC mutant enzymes typically have reduced specific activity and reduced lysosomal concentration, the latter due to compromised folding in the endoplasmic reticulum (ER) and trafficking to the lysosome. Recently, we and others have demonstrated that pharmacological chaperones bind to the active site and assist folding of GC variants in the ER, enable their trafficking to the lysosome, and increase the cellular GC enzyme activity. Pharmacological chaperones represent a desirable alternative strategy because of the likelihood that orally available compounds that cross the blood-brain barrier can be developed. Here, we successfully combined in silico virtual screening methodology and experimental validation followed by rational drug design to discovery potent pharmacological chaperone leads. These leads are desirable for further optimization. The protocol presented here is also applicable to other areas of structure-based drug design.
 

General Oral Session
1:30 PM-4:50 PM, Thursday, August 23, 2007 BCEC -- 210A, Oral

Division of Medicinal Chemistry

The 234th ACS National Meeting, Boston, MA, August 19-23, 2007