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    Common ligand mimics: pseudothiohydantoins
    1.
    发明申请
    Common ligand mimics: pseudothiohydantoins 审中-公开
    普通配体模拟物：假硫代乙内酰脲

    公开(公告)号：US20050019825A9

    公开(公告)日：2005-01-27

    申请号：US10099136

    申请日：2002-03-15

    申请人： Qing Dong ,  Fabrice Pierre ,  Hengyuan Lang ,  Lin Yu ,  Mark Hansen ,  Daniel Sem ,  Maurizio Pellecchia

    发明人： Qing Dong ,  Fabrice Pierre ,  Hengyuan Lang ,  Lin Yu ,  Mark Hansen ,  Daniel Sem ,  Maurizio Pellecchia

    IPC分类号： C07B61/00 ,  C07D277/20 ,  C07D277/38 ,  C07D417/06 ,  C07D417/12 ,  G01N33/53 ,  C07D417/02 ,  G01N33/543

    CPC分类号： C07D277/20 ,  C07D417/06 ,  C07D417/12 ,  C40B40/00 ,  G01N2500/00

    摘要： The present invention provides common ligand mimics that act as common ligands for a receptor family. The present invention also provides bi-ligands containing these common ligand mimics. Bi-ligands of the invention provide enhanced affinity and/or selectivity of ligand binding to a receptor or receptor family through the synergistic action of the common ligand mimic and specificity ligand that compose the bi-ligand. The present invention also provides combinatorial libraries containing the common ligand mimics and bi-ligands of the invention. Further, the present invention provides methods for manufacturing the common ligand mimics and bi-ligands of the invention and methods for assaying the combinatorial libraries of the invention.

    摘要翻译： 本发明提供了作为受体家族的共同配体的常见配体模拟物。 本发明还提供含有这些共同配体模拟物的双配体。 本发明的双配体通过构成双配体的共同配体模拟物和特异性配体的协同作用，提供配体与受体或受体家族结合的增强的亲和力和/或选择性。 本发明还提供了包含本发明的共同配体模拟物和双配位体的组合文库。 此外，本发明提供了制备本发明的共同配体模拟物和双配位体的方法以及用于测定本发明的组合文库的方法。

    NMR-solve method for rapid identification of bi-ligand drug candidates
    3.
    发明申请
    NMR-solve method for rapid identification of bi-ligand drug candidates 有权
    用于快速鉴定双配体药物候选物的NMR-解决方法

    公开(公告)号：US20050112716A1

    公开(公告)日：2005-05-26

    申请号：US10884181

    申请日：2004-07-02

    申请人： Daniel Sem ,  Maurizio Pellecchia ,  Anna Tempczyk-Russell

    发明人： Daniel Sem ,  Maurizio Pellecchia ,  Anna Tempczyk-Russell

    IPC分类号： C12Q1/32 ,  G01N33/53 ,  G01N33/542 ,  G01N33/68 ,  C12Q1/68 ,  G01N33/48 ,  G01N33/50 ,  G06F19/00

    CPC分类号： C12Q1/00 ,  C12Q1/32 ,  C12Q1/485 ,  G01N33/53 ,  G01N33/542 ,  G01N33/6803 ,  G01N2500/00 ,  G01N2500/20 ,  Y10T436/24

    摘要： Methods for rapidly identifying drug candidates that can bind to an enzyme at both a common ligand site and a specificity ligand site, resulting in high affinity binding. The bi-ligand drug candidates are screened from a focused combinatorial library where the specific points of variation on a core structure are optimized. The optimal points of variation are identified by which atoms of a ligand bound to the common ligand site are identified to be proximal to the specificity ligand site. As a result, the atoms proximal to the specificity ligand site can then be used as a point for variation to generate a focused combinatorial library of high affinity drug candidates that can bind to both the common ligand site and the specificity ligand site. Different candidates in the library can then have high affinity for many related enzymes sharing a similar common ligand site.

    摘要翻译： 用于快速鉴定可以在共同配体位点和特异性配体位点处结合酶的候选药物的方法，导致高亲和力结合。 双重配体药物候选物从聚焦的组合文库筛选，其中优化核心结构上的特异性变异点。 通过与共同配体位点结合的配体的哪个原子被鉴定为接近特异性配体位点来鉴定最佳的变化点。 结果，接近特异性配体位点的原子然后可以用作变异点，以产生可以结合共同配体位点和特异性配体位点的高亲和力药物候选物的聚焦组合文库。 然后，文库中的不同候选物可以对共享相似共同配体位点的许多相关酶具有高亲和力。

    Sea-trosy and related methods
    4.
    发明申请
    Sea-trosy and related methods 审中-公开
    海y和相关方法

    公开(公告)号：US20060166279A1

    公开(公告)日：2006-07-27

    申请号：US11320157

    申请日：2005-12-27

    申请人： Daniel Sem ,  Maurizio Pellecchia

    发明人： Daniel Sem ,  Maurizio Pellecchia

    IPC分类号： G01N33/53

    CPC分类号： G01R33/4608 ,  G01R33/465 ,  Y10T436/24

    摘要： A method for preferentially observing an exposed position (1c) of a macromolecule. A sample is obtained having a macromolecule (1a) with a first proton (1) and a second molecule (2a) with a second proton (2); then applying a magnetic field (4) to the sample and irradiating the sample with a pulse sequence (5) that preferentially demagnetizes protons of the macromolecule (1,3) relative to the second proton (2); allowing the second proton (2) to exchange (6) with an exposed proton (1) of the macromolecule; and detecting the magnetization from the relatively magnetized second proton (2), which is now bound to the exposed position (1c) of the macromolecule. The invention also provides a method for observing a position in the macromolecule that bind a ligand.

    摘要翻译： 优选观察高分子暴露位置（1c）的方法。 获得具有第一质子（1）的大分子（1a）和具有第二质子（2）的第二分子（2a）的样品; 然后对样品施加磁场（4）并用脉冲序列（5）照射样品，所述脉冲序列（5）相对于第二质子（2）优先地消磁高分子（1,3）的质子; 允许第二质子（2）与大分子的暴露的质子（1）交换（6）; 并且检测来自相对磁化的第二质子（2）的磁化，其现在与大分子的暴露位置（1c）结合。 本发明还提供了观察结合配体的大分子中的位置的方法。

    NMR-SOLVE METHOD FOR RAPID IDENTIFICATION OF BI-LIGAND DRUG CANDIDATES
    5.
    发明申请
    NMR-SOLVE METHOD FOR RAPID IDENTIFICATION OF BI-LIGAND DRUG CANDIDATES 审中-公开
    用于快速鉴定双配偶药物候选药物的NMR-溶解方法

    公开(公告)号：US20070298439A1

    公开(公告)日：2007-12-27

    申请号：US11833191

    申请日：2007-08-02

    申请人： Daniel Sem ,  Maurizio Pellecchia ,  Anna Tempczyk-Russell

    发明人： Daniel Sem ,  Maurizio Pellecchia ,  Anna Tempczyk-Russell

    IPC分类号： G01N33/573

    CPC分类号： C12Q1/00 ,  C12Q1/32 ,  C12Q1/485 ,  G01N33/53 ,  G01N33/542 ,  G01N33/6803 ,  G01N2500/00 ,  G01N2500/20 ,  Y10T436/24

    摘要： Methods for rapidly identifying drug candidates that can bind to an enzyme at both a common ligand site and a specificity ligand site, resulting in high affinity binding. The bi-ligand drug candidates are screened from a focused combinatorial library where the specific points of variation on a core structure are optimized. The optimal points of variation are identified by which atoms of a ligand bound to the common ligand site are identified to be proximal to the specificity ligand site. As a result, the atoms proximal to the specificity ligand site can then be used as a point for variation to generate a focused combinatorial library of high affinity drug candidates that can bind to both the common ligand site and the specificity ligand site. Different candidates in the library can then have high affinity for many related enzymes sharing a similar common ligand site.

    摘要翻译： 用于快速鉴定可以在共同配体位点和特异性配体位点处结合酶的候选药物的方法，导致高亲和力结合。 双重配体药物候选物从聚焦的组合文库筛选，其中优化核心结构上的特异性变异点。 通过与共同配体位点结合的配体的哪个原子被鉴定为接近特异性配体位点来鉴定最佳的变化点。 结果，接近特异性配体位点的原子然后可以用作变异点，以产生可以结合共同配体位点和特异性配体位点的高亲和力药物候选物的聚焦组合文库。 然后，文库中的不同候选物可以对共享相似共同配体位点的许多相关酶具有高亲和力。

    Nuclear magnetic resonance-docking of compounds
    6.
    发明申请
    Nuclear magnetic resonance-docking of compounds 审中-公开
    化合物的核磁共振对接

    公开(公告)号：US20050234652A1

    公开(公告)日：2005-10-20

    申请号：US11115850

    申请日：2005-04-26

    申请人： Daniel Sem ,  Maurizio Pellecchia

    发明人： Daniel Sem ,  Maurizio Pellecchia

    IPC分类号： G01N24/08 ,  G01R33/46 ,  G01R33/465 ,  G06F19/00 ,  G01N33/48 ,  G01N33/50

    CPC分类号： G01N24/08 ,  G01R33/4625 ,  G01R33/465 ,  Y10T436/24

    摘要： The invention provides a method for determining a structure model for a test ligand bound to a macromolecule binding site. Structural constraints for the test ligand are derived from spectroscopic signals arising from interactions between the test ligand and macromolecule. The structure constraints are used as constraints in docking a structure model of the ligand to a structure model of the macromolecule, or as constraints in overlaying a structure model of the test ligand on the known structure for a reference ligand that binds to the macromolecule. The invention further provides a method for determining a structure model for a macromolecule bound to a ligand. Structural constraints derived from spectroscopically observed interactions of the macromolecule and a reference ligand are used to guide molecular modeling or to evaluate the results of a molecular modeling simulation of the macromolecule.

    摘要翻译： 本发明提供了一种确定与大分子结合位点结合的测试配体的结构模型的方法。 测试配体的结构约束来源于由测试配体和大分子之间的相互作用产生的光谱信号。 结构约束被用作将配体的结构模型对接到大分子的结构模型的约束，或作为将测试配体的结构模型重叠在与大分子结合的参考配体的已知结构上的限制。 本发明还提供了一种用于测定与配体结合的大分子的结构模型的方法。 用大分子和参考配体的光谱观察相互作用衍生的结构约束用于指导分子建模或评估大分子的分子模拟模拟的结果。

    Nuclear magnetic resonance assembly of chemical entities
    7.
    发明授权
    Nuclear magnetic resonance assembly of chemical entities 失效
    化学实体的核磁共振组件

    公开(公告)号：US07653490B2

    公开(公告)日：2010-01-26

    申请号：US10172485

    申请日：2002-06-13

    申请人： Daniel S. Sem ,  Maurizio Pellecchia ,  Qing Dong ,  Mark Kelly ,  Min S. Lee

    发明人： Daniel S. Sem ,  Maurizio Pellecchia ,  Qing Dong ,  Mark Kelly ,  Min S. Lee

    IPC分类号： G06F7/00

    CPC分类号： G01N33/542 ,  G01N24/08

    摘要： The invention provides a method for obtaining a binding compound for a protein family, wherein the members of the protein family bind a common ligand. The method includes the steps of (a) providing a sample containing a protein from the protein family, a first ligand and a second ligand under conditions wherein the first ligand, the second ligand and the protein form a bound complex; (b) detecting magnetization transfer between the first ligand and the second ligand in the bound complex, thereby determining that the two ligands are proximal in the bound complex; and (c) obtaining a candidate binding compound including the first ligand, or a fragment thereof linked to the second ligand, or a homolog thereof, whereby the population contains binding compounds that bind to members of the protein family.

    摘要翻译： 本发明提供了一种获得蛋白质家族的结合化合物的方法，其中蛋白质家族的成员结合共同的配体。 该方法包括以下步骤：（a）在第一配体，第二配体和蛋白质形成结合复合物的条件下，提供含有来自蛋白质家族的蛋白质的样品，第一配体和第二配体; （b）检测结合的络合物中第一配体和第二配体之间的磁化转移，由此确定两个配体在结合复合物中的近端; 和（c）获得包含与第二配体连接的第一配体或其片段或其同系物的候选结合化合物，其中所述群体含有结合蛋白家族成员的结合化合物。

    SELECTIVE INHIBITORS OF AKT AND METHODS OF USING SAME
    8.
    发明申请
    SELECTIVE INHIBITORS OF AKT AND METHODS OF USING SAME 审中-公开
    AKT的选择性抑制剂及其使用方法

    公开(公告)号：US20120190707A1

    公开(公告)日：2012-07-26

    申请号：US13357541

    申请日：2012-01-24

    申请人： Ze'ev Ronai ,  Maurizio Pellecchia ,  Gary Chiang

    发明人： Ze'ev Ronai ,  Maurizio Pellecchia ,  Gary Chiang

    IPC分类号： A61K31/4709 ,  C07D471/04 ,  C07D401/10 ,  A61K31/4704 ,  A61P35/00 ,  A61P25/28 ,  C07D401/06 ,  C07D215/227

    CPC分类号： A61K31/415 ,  A61K31/47 ,  C07D215/227 ,  C07D307/46 ,  C07D401/06 ,  C07D405/06

    摘要： The present invention describes an improved method for screening compounds for activity in inhibiting the enzymatic activity of Akt1 protein kinase. In general, the method comprises: (1) providing a plurality of compounds suspected of having Akt1 kinase inhibitory activity; (2) modeling the docking of each of the plurality of the compounds with a target binding site; (3) ranking the docked compounds by goodness of fit; (4) further selecting compounds; (5) optionally, visually analyzing structures of compounds selected in step (4) to remove any compounds with improbable docking geometry; and (6) experimentally testing the selected compounds from step (4) or step (5), if step (5) is performed, to determine their inhibitory activity against Akt1. The invention also encompasses pharmaceutical compositions including compounds whose inhibitory activity against Akt1 is discovered by the screening method, as well as methods of use of the pharmaceutical compositions to prevent and treat cancer and other conditions.

    摘要翻译： 本发明描述了一种用于筛选化合物以抑制Akt1蛋白激酶的酶活性的活性的改进方法。 通常，该方法包括：（1）提供疑似具有Akt1激酶抑制活性的多种化合物; （2）建模多个化合物中的每一个与靶结合位点的对接; （3）通过拟合优点对准对接化合物; （4）进一步选择化合物; （5）任选地，目视分析在步骤（4）中选择的化合物的结构以除去具有不可能的对接几何形状的任何化合物; 和（6）如果进行步骤（5），则从步骤（4）或步骤（5）中实验测试所选择的化合物，以确定其对Akt1的抑制活性。 本发明还包括药物组合物，包括通过筛选方法发现对Akt1的抑制活性的化合物，以及药物组合物用于预防和治疗癌症和其它病症的方法。