2v00: Difference between revisions

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.

2V00 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Cryphonectria_parasitica Cryphonectria parasitica] with <scene name='pdbligand=ACT:'>ACT</scene>, <scene name='pdbligand=V15:'>V15</scene> and <scene name='pdbligand=GOL:'>GOL</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Endothiapepsin Endothiapepsin], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.23.22 3.4.23.22] Known structural/functional Sites: <scene name='pdbsite=AC1:Gol Binding Site For Chain A'>AC1</scene>, <scene name='pdbsite=AC2:Gol Binding Site For Chain A'>AC2</scene>, <scene name='pdbsite=AC3:Gol Binding Site For Chain A'>AC3</scene>, <scene name='pdbsite=AC4:Act Binding Site For Chain A'>AC4</scene>, <scene name='pdbsite=AC5:Act Binding Site For Chain A'>AC5</scene> and <scene name='pdbsite=AC6:V15 Binding Site For Chain A'>AC6</scene>. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2V00 OCA].  

Discovery of a Novel Warhead against beta-Secretase through Fragment-Based Lead Generation., Geschwindner S, Olsson LL, Albert JS, Deinum J, Edwards PD, Beer T, Folmer RH, J Med Chem. 2007 Nov 29;50(24):5903-11. Epub 2007 Nov 7. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=17985861 17985861]

[[Category: Albert, J.S.]]

[[Category: Beer, T.De.]]

[[Category: Edwards, P.D.]]

[[Category: Folmer, R.H.A.]]

[[Category: Olsson, L.L.]]

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