Patent ID: 7630838

Claim:
A method for identifying a candidate agent that interacts with or binds to a beta-amyloid precursor protein (APP) binding site of Beta-site APP Cleaving Enzyme (BACE), the method comprising: (a) utilizing the relative three-dimensional structural coordinates of a complex of a BACE peptide and an APP inhibitor peptide according to FIGS. 1 A- 1 EEE, ±a root mean square deviation from the backbone atoms of the amino acid residues in the complex not more than 1.5 {acute over (Å)}, to generate a three-dimensional representation of the complex, wherein: (i) the BACE peptide in the complex comprises the amino acid sequence of residues 58-447 of SEQ ID NO: 1, and (ii) the APP inhibitor peptide in the complex comprises the amino acid sequence SEVNStaVAEF (SEQ ID NO:3), wherein Sta is (S)-statine; (b) identifying the amino acid residues forming the APP binding site of the BACE peptide from the three-dimensional representation in step (a), wherein the APP-binding site comprises the relative structural coordinates according to FIGS. 1 A- 1 EEE of amino acid residues LYS70, SER71, GLY72, GLN73, GLY74, TYR75, LEU91, VAL92, ASP93, THR94, GLY95, SER96, SER97, ASN98, TYR129, VAL130, PRO131, TYR132, THR133, GLN134, GLY135, LYS136, TRP137, LYS168, PHE169, PHE170, ILE171, ASN172, SER174, TRP176, GLY178, ILE179, LEU180, GLY181, ALA183, TYR184, ALA185, GLU186, ILE187, ALA188, ARG189, PRO190, ASP191, ASP192, ARG256, TRP258, TYR259, TYR283, ASP284, LYS285, SER286, ILE287, VAL288, ASP289, SER290, GLY291, THR292, THR293, ASN294, LEU295, ARG296, GLY325, GLU326, ARG368, VAL370, LYS382, PHE383, ALA384, ILE385, SER386, GLN387, SER388, SER389, THR390, GLY391, THR392, VAL393, GLY395, ALA396, and ILE447, ±a root mean square deviation from the backbone atoms of said amino acid residues of not more than 1.5 {acute over (Å)}; (c) generating a three-dimensional model of the APP binding site of BACE; (d) employing said three-dimensional model from step (c) to identify said candidate agent; (e) obtaining said candidate agent; and (f) contacting in vitro or in vivo said candidate agent with BACE to determine the ability of said candidate agent to interact or bind to BACE, whereby the detection of the ability of said candidate agent to interact or bind to BACE identifies said candidate agent.