2V00

X-ray crystal structure of endothiapepsin complexed with compound 1

Summary for 2V00

• Entry DOI: 10.2210/pdb2v00/pdb
• Related: 1E5O 1E80 1E81 1E82 1EED 1ENT 1GKT 1GVT 1GVU 1GVV 1GVW 1GVX 1OD1 1OEW 1OEX
• Descriptor: ENDOTHIAPEPSIN, GLYCEROL, ACETATE ION, ... (5 entities in total)
• Functional Keywords: fragment hit, b- secretase, endothiapepsin, bace, zymogen, protease, hydrolase, isocytosine, alzheimer's disease, fragment-based lead generation, aspartyl protease, surrogate protein
• Biological source: CRYPHONECTRIA PARASITICA (CHESTNUT BLIGHT FUNGUS)
• Total number of polymer chains: 1
• Total formula weight: 34423.48

Authors

Geschwindner, S.,Olsson, L.L.,Deinum, J.,Albert, J.S.,Edwards, P.D.,De Beer, T.,Folmer, R.H.A. (deposition date: 2007-05-03, release date: 2007-12-04, Last modification date: 2024-11-13)

Primary citation

Geschwindner, S.,Olsson, L.L.,Albert, J.S.,Deinum, J.,Edwards, P.D.,De Beer, T.,Folmer, R.H.A.
Discovery of a Novel Warhead Against Beta-Secretase Through Fragment-Based Lead Generation.
J.Med.Chem., 50:5903-, 2007

PubMed Abstract: Fragment-based lead generation was applied to find novel small-molecule inhibitors of beta-secretase (BACE-1), a key target for the treatment of Alzheimer's disease. Fragment hits coming from a 1D NMR screen were characterized by BIAcore, and the most promising compounds were soaked into protein crystals to help the rational design of more potent hit analogues. Problems arising due to our inability to grow BACE-1 crystals at the biologically relevant pH at which the screen was run were overcome by using endothiapepsin as a surrogate aspartyl protease. Among others, we identified 6-substituted isocytosines as a novel warhead against BACE-1, and the accompanying paper in this journal describes how these were optimized to a lead series of nanomolar inhibitors.1.

PubMed: 17985861
DOI: 10.1021/JM070825K

Experimental method

X-RAY DIFFRACTION (1.55 Å)