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    • 2. 发明申请
    • METHOD OF DRUG SELECTION
    • WO9909417A3
    • 1999-08-12
    • PCT/GB9802510
    • 1998-08-20
    • NYCOMED IMAGING ASCOCKBAIN JULIANWOLFE HENRY RAPHAEL
    • WOLFE HENRY RAPHAEL
    • G01N33/50A61K38/00C07K1/04C40B30/04G01N20060101G01N33/15G01N33/566G01N33/68
    • C40B30/04C07K1/047G01N33/6845G01N2333/245
    • The invention provides a method for selecting a candidate drug compound, said method comprising i) identifying a starting oligopeptide having a binding affinity for a cell surface or other receptor site; ii) generating a plurality of homologous oligopeptides having single site amino acid modifications relative to said starting oligopeptide; iii) identifying components of said starting oligopeptide responsible for the secondary structure thereof; iv) for modification sites identified in step (ii) selecting a set of amino acids; v) for components identified in step (iii) selecting at least one non-natural amino acid which mimics the secondary structure of the component; vi) generating a first combinatorial library of oligopeptides having at said identified modification sites amino acid residues corresponding to said selected sets of amino acids; vii) identifying members of said first library having a binding affinity value above a predetermined minimum and generating a further combinatorial library of oligopeotides having members not present in said first library, and identifying members of said further library having improved binding affinity values relative to the identified members of said first library, and with the proviso that at least one of said first and further libraries contains oligopeptides containing residues of said non-natural amino acid or acids; and (viii) selecting from the identified members of said library or library a drug candidate.
    • 3. 发明申请
    • METHOD OF DRUG SELECTION
    • 药物选择方法
    • WO9909417A9
    • 1999-05-27
    • PCT/GB9802510
    • 1998-08-20
    • NYCOMED IMAGING ASCOCKBAIN JULIANWOLFE HENRY RAPHAEL
    • WOLFE HENRY RAPHAEL
    • G01N33/50A61K38/00C07K1/04C40B30/04G01N20060101G01N33/15G01N33/566G01N33/68
    • C40B30/04C07K1/047G01N33/6845G01N2333/245
    • The invention provides a method for selecting a candidate drug compound, said method comprising i) identifying a starting oligopeptide having a binding affinity for a cell surface or other receptor site; ii) generating a plurality of homologous oligopeptides having single site amino acid modifications relative to said starting oligopeptide; iii) identifying components of said starting oligopeptide responsible for the secondary structure thereof; iv) for modification sites identified in step (ii) selecting a set of amino acids; v) for components identified in step (iii) selecting at least one non-natural amino acid which mimics the secondary structure of the component; vi) generating a first combinatorial library of oligopeptides having at said identified modification sites amino acid residues corresponding to said selected sets of amino acids; vii) identifying members of said first library having a binding affinity value above a predetermined minimum and generating a further combinatorial library of oligopeotides having members not present in said first library, and identifying members of said further library having improved binding affinity values relative to the identified members of said first library, and with the proviso that at least one of said first and further libraries contains oligopeptides containing residues of said non-natural amino acid or acids; and (viii) selecting from the identified members of said library or library a drug candidate.
    • 本发明提供了用于选择候选药物化合物的方法,所述方法包括:i)鉴定对细胞表面或其他受体位点具有结合亲和力的起始寡肽; ii)产生相对于所述起始寡肽具有单位点氨基酸修饰的多个同源寡肽; iii)鉴定负责其二级结构的所述起始寡肽的组分; iv)在步骤(ii)中鉴定的修饰位点选择一组氨基酸; v)对于步骤(iii)中鉴定的组分,选择至少一种模拟组分二级结构的非天然氨基酸; vi)产生寡肽的第一组合文库,其在所述鉴定的修饰位点处具有对应于所述选择的氨基酸组的氨基酸残基; vii)鉴定具有高于预定最小值的结合亲和力值的所述第一文库的成员,并产生具有不存在于所述第一文库中的成员的寡核苷酸的另一组合文库,并鉴定所述另外文库相对于所鉴定的具有改善的结合亲和力值的成员 所述第一文库的成员,并且附带条件是所述第一文库和其他文库中的至少一个包含含有所述非天然氨基酸残基的寡肽; 和(viii)从所述图书馆或图书馆的特定成员中选择候选药物。