公开(公告)号：US07756674B2

公开(公告)日：2010-07-13

申请号：US11982783

申请日：2007-11-05

申请人： Thomas Young ,  Robert Abel ,  Richard A. Friesner ,  Bruce J. Berne

发明人： Thomas Young ,  Robert Abel ,  Richard A. Friesner ,  Bruce J. Berne

IPC分类号： G06F17/18 ,  G01N33/53

CPC分类号： G06F19/706 ,  G06F19/704 ,  G06F19/708

摘要： Described is a technique to exhaustively enumerate the thermodynamic properties of the water molecules solvating the active site of a protein in its apostate and calculate the relative binding affinities of congeneric compounds that bind to this protein. The subject matter includes sampling the configurations of the solvating water in the active site; extracting the thermodynamic information about the solvating water from these configurations by clustering the observed water configurations into regions of high water occupancy (e.g., “hydration sites”), computing the average system interaction energies of water molecules occupying the various hydrations sites, computing excess entropies of water molecules occupying the hydration sites; constructing a 3 dimensional hydration thermodynamics map of the protein active site; and computing relative binding affinities of congeneric ligands based on the principle that tighter binding ligands can displace more entropically structured and energetically depleted hydration sites from the active site into the bulk fluid.

摘要翻译： 描述了一种全面列举溶剂化其脱保护素中蛋白质的活性位点的水分子的热力学性质并计算结合该蛋白质的同源化合物的相对结合亲和力的技术。 主题包括抽取活性部位溶剂化水的结构; 通过将观察到的水配置聚集到高占有率的区域（例如“水合位点”），从这些构造提取溶解水的热力学信息，计算占据各种水合位点的水分子的平均系统相互作用能量，计算过量熵 的水分子占据水合位置; 构建蛋白活性位点的三维水合热力学图; 并计算同源配体的相对结合亲和力，其原理是更紧密的结合配体可以将更多的熵结构化和能量耗尽的水合位点从活性位点移动到体液中。

公开(公告)号：US07970581B2

公开(公告)日：2011-06-28

申请号：US12791493

申请日：2010-06-01

申请人： Thomas Young ,  Robert Abel ,  Richard A. Friesner ,  Bruce J. Berne

发明人： Thomas Young ,  Robert Abel ,  Richard A. Friesner ,  Bruce J. Berne

IPC分类号： G01N33/48

CPC分类号： G06F19/706 ,  G06F19/704 ,  G06F19/708

摘要： Described is a technique to exhaustively enumerate the thermodynamic properties of the water molecules solvating the active site of a protein in its apostate and calculate the relative binding affinities of congeneric compounds that bind to this protein. The subject matter includes sampling the configurations of the solvating water in the active site; extracting the thermodynamic information about the solvating water from these configurations by clustering the observed water configurations into regions of high water occupancy (e.g., “hydration sites”), computing the average system interaction energies of water molecules occupying the various hydrations sites, computing excess entropies of water molecules occupying the hydration sites; constructing a 3 dimensional hydration thermodynamics map of the protein active site; and computing relative binding affinities of congeneric ligands based on the principle that tighter binding ligands can displace more entropically structured and energetically depleted hydration sites from the active site into the bulk fluid.

摘要翻译： 描述了一种全面列举溶剂化其脱保护素中蛋白质的活性位点的水分子的热力学性质并计算结合该蛋白质的同源化合物的相对结合亲和力的技术。 主题包括抽取活性部位溶剂化水的结构; 通过将观察到的水配置聚集到高占有率的区域（例如“水合位点”），从这些构造提取溶解水的热力学信息，计算占据各种水合位点的水分子的平均系统相互作用能量，计算过量熵 的水分子占据水合位置; 构建蛋白活性位点的三维水合热力学图; 并计算同源配体的相对结合亲和力，其原理是更紧密的结合配体可以将更多的熵结构化和能量耗尽的水合位点从活性位点移动到体液中。

公开(公告)号：US20090037136A1

公开(公告)日：2009-02-05

申请号：US11982783

申请日：2007-11-05

申请人： Thomas Young ,  Robert Abel ,  Richard A. Friesner ,  Bruce J. Berne

发明人： Thomas Young ,  Robert Abel ,  Richard A. Friesner ,  Bruce J. Berne

IPC分类号： G01K13/00 ,  G06F17/18

CPC分类号： G06F19/706 ,  G06F19/704 ,  G06F19/708

摘要： Described is a technique to exhaustively enumerate the thermodynamic properties of the water molecules solvating the active site of a protein in its apostate and calculate the relative binding affinities of congeneric compounds that bind to this protein. The subject matter includes sampling the configurations of the solvating water in the active site; extracting the thermodynamic information about the solvating water from these configurations by clustering the observed water configurations into regions of high water occupancy (e.g., “hydration sites”), computing the average system interaction energies of water molecules occupying the various hydrations sites, computing excess entropies of water molecules occupying the hydration sites; constructing a 3 dimensional hydration thermodynamics map of the protein active site; and computing relative binding affinities of congeneric ligands based on the principle that tighter binding ligands can displace more entropically structured and energetically depleted hydration sites from the active site into the bulk fluid.

摘要翻译： 描述了一种全面列举溶剂化其脱保护素中蛋白质的活性位点的水分子的热力学性质并计算结合该蛋白质的同源化合物的相对结合亲和力的技术。 主题包括抽取活性部位溶剂化水的结构; 通过将观察到的水配置聚集到高占有率的区域（例如“水合位点”），从这些构造提取溶解水的热力学信息，计算占据各种水合位点的水分子的平均系统相互作用能量，计算过量熵 的水分子占据水合位置; 构建蛋白活性位点的三维水合热力学图; 并计算同源配体的相对结合亲和力，其原理是更紧密的结合配体可以将更多的熵结构化和能量耗尽的水合位点从活性位点移动到体液中。

公开(公告)号：US07970580B2

公开(公告)日：2011-06-28

申请号：US12791448

申请日：2010-06-01

申请人： Thomas Young ,  Robert Abel ,  Richard A. Friesner ,  Bruce J. Berne

发明人： Thomas Young ,  Robert Abel ,  Richard A. Friesner ,  Bruce J. Berne

IPC分类号： G01N33/48

CPC分类号： G06F19/706 ,  G06F19/704 ,  G06F19/708

摘要： Described is a technique to exhaustively enumerate the thermodynamic properties of the water molecules solvating the active site of a protein in its apostate and calculate the relative binding affinities of congeneric compounds that bind to this protein. The subject matter includes sampling the configurations of the solvating water in the active site; extracting the thermodynamic information about the solvating water from these configurations by clustering the observed water configurations into regions of high water occupancy (e.g., “hydration sites”), computing the average system interaction energies of water molecules occupying the various hydrations sites, computing excess entropies of water molecules occupying the hydration sites; constructing a 3 dimensional hydration thermodynamics map of the protein active site; and computing relative binding affinities of congeneric ligands based on the principle that tighter binding ligands can displace more entropically structured and energetically depleted hydration sites from the active site into the bulk fluid.

公开(公告)号：US20100241412A1

公开(公告)日：2010-09-23

申请号：US12791493

申请日：2010-06-01

申请人： Thomas Young ,  Robert Abel ,  Richard A. Friesner ,  Bruce J. Berne

发明人： Thomas Young ,  Robert Abel ,  Richard A. Friesner ,  Bruce J. Berne

IPC分类号： G06G7/58

CPC分类号： G06F19/706 ,  G06F19/704 ,  G06F19/708

摘要： Described is a technique to exhaustively enumerate the thermodynamic properties of the water molecules solvating the active site of a protein in its apostate and calculate the relative binding affinities of congeneric compounds that bind to this protein. The subject matter includes sampling the configurations of the solvating water in the active site; extracting the thermodynamic information about the solvating water from these configurations by clustering the observed water configurations into regions of high water occupancy (e.g., “hydration sites”), computing the average system interaction energies of water molecules occupying the various hydrations sites, computing excess entropies of water molecules occupying the hydration sites; constructing a 3 dimensional hydration thermodynamics map of the protein active site; and computing relative binding affinities of congeneric ligands based on the principle that tighter binding ligands can displace more entropically structured and energetically depleted hydration sites from the active site into the bulk fluid.

公开(公告)号：US20100241411A1

公开(公告)日：2010-09-23

申请号：US12791448

申请日：2010-06-01

申请人： Thomas Young ,  Robert Abel ,  Richard A. Friesner ,  Bruce J. Berne

发明人： Thomas Young ,  Robert Abel ,  Richard A. Friesner ,  Bruce J. Berne

IPC分类号： G06G7/58

CPC分类号： G06F19/706 ,  G06F19/704 ,  G06F19/708

摘要： Described is a technique to exhaustively enumerate the thermodynamic properties of the water molecules solvating the active site of a protein in its apostate and calculate the relative binding affinities of congeneric compounds that bind to this protein. The subject matter includes sampling the configurations of the solvating water in the active site; extracting the thermodynamic information about the solvating water from these configurations by clustering the observed water configurations into regions of high water occupancy (e.g., “hydration sites”), computing the average system interaction energies of water molecules occupying the various hydrations sites, computing excess entropies of water molecules occupying the hydration sites; constructing a 3 dimensional hydration thermodynamics map of the protein active site; and computing relative binding affinities of congeneric ligands based on the principle that tighter binding ligands can displace more entropically structured and energetically depleted hydration sites from the active site into the bulk fluid.

摘要翻译： 描述了一种全面列举溶剂化其脱保护素中蛋白质的活性位点的水分子的热力学性质并计算结合该蛋白质的同源化合物的相对结合亲和力的技术。 主题包括抽取活性部位溶剂化水的结构; 通过将观察到的水配置聚集到高占有率的区域（例如“水合位点”），从这些构造提取溶解水的热力学信息，计算占据各种水合位点的水分子的平均系统相互作用能量，计算过量熵 的水分子占据水合位置; 构建蛋白活性位点的三维水合热力学图; 并计算同源配体的相对结合亲和力，其原理是更紧密的结合配体可以将更多的熵结构化和能量耗尽的水合位点从活性位点移动到体液中。

公开(公告)号：US09858395B2

公开(公告)日：2018-01-02

申请号：US13113506

申请日：2011-05-23

申请人： Richard A. Friesner ,  Robert Murphy

发明人： Richard A. Friesner ,  Robert Murphy

IPC分类号： G06F19/00 ,  G06F19/10

CPC分类号： G06F19/706

摘要： A method of scoring binding affinity of a proposed ligand molecule for a receptor molecule using computer analysis and computer data bases to accounts for the increase in energy required where docking disrupts or partially disrupts the π-conjugated character of the ligand when bound to the receptor. The method uses data representing one or more proposed ligand molecules to be scored and data representing the receptor molecule. Computer analysis of the proposed ligand molecule data determines whether the ligand includes at least one π-conjugated moiety having multiple possible geometries, one of those geometries being characterized by less delocalization of electrons across the π-conjugated moiety than the delocalization of electrons characterizing another of those geometries. Computer analysis of the predicted ligand-receptor structure determines whether the ligand in the ligand-receptor structure adopts the geometry characterized by less delocalization. If so, a penalty is explicitly imposed for reduced delocalization of electrons across the π-conjugated moieties.

公开(公告)号：US08145430B2

公开(公告)日：2012-03-27

申请号：US11373684

申请日：2006-03-10

申请人： Richard A. Friesner ,  Robert Murphy

发明人： Richard A. Friesner ,  Robert Murphy

IPC分类号： G06G7/48 ,  G06G7/58

CPC分类号： G06F19/706 ,  C40B30/02 ,  G06F19/16 ,  G06F19/18 ,  G06F19/26

摘要： A computer-implemented method for calculating a value representative of interaction (VRI) of a proposed ligand with a specified receptor. Hydrophobic interactions between one or more ligand atoms and one or more receptor atoms are scored by a method that awards a bonus for the presence of hydrophobic enclosure of one or more ligand atoms by the receptor. Also, charge-charge hydrogen bonds between a ligand and a receptor are scored by setting a default value for a charge-charge hydrogen bond and awarding a bonus above the default value when one or more specialized predetermined charge-charge hydrogen bond criteria is satisfied. Various charge-charge hydrogen bond criteria are used. Zwitterions, charge, salvation, geometry and electrostatic energy are accounted for.

摘要翻译： 一种计算机实现的方法，用于计算代表所提及的配体与指定受体的相互作用（VRI）的值。 通过一种方法来评估一个或多个配体原子和一个或多个受体原子之间的疏水相互作用，所述方法为受体的一个或多个配体原子的疏水封闭的存在赋予奖励。 此外，通过设定充电氢氢键的默认值，并且当满足一个或多个专门的预定充电氢键标准时，将奖金高于默认值来评分配体和受体之间的充电氢键。 使用各种充电氢键标准。 两性离子，电荷，溶剂化，几何形状和静电能量。

公开(公告)号：US20080312894A1

公开(公告)日：2008-12-18

申请号：US12152067

申请日：2008-05-12

申请人： Richard A. Friesner ,  Robert Murphy

发明人： Richard A. Friesner ,  Robert Murphy

IPC分类号： G06G7/58

CPC分类号： G06F19/706 ,  G06F19/16 ,  G06F19/707

摘要： Scoring functions can be markedly improved by taking into account the status environs of ligand rings (or indeed other bulky rigid ligand structures) on the ligand when the ligand is complexed with the receptor. In its most general form, the invention features, quantifying a particular component of binding affinity between a ligand and a receptor molecule. Specifically, the component in question takes into account the spatial relationship between ligand ring structure(s) (or bulky rigid ligand structures) and their ambient surroundings when the ligand is bound to the receptor molecule. The method steps may be used when quantifying a component that reflects these particular ligand features alone, or the steps may be part of a comprehensive method of quantifying binding affinity which includes numerous other factors that relate to binding affinity in addition to the component. For example, one may calculate an initial binding affinity and then adjust the initial binding affinity by a factor obtained at least in part based on the classification of the ring structure.

摘要翻译： 当配体与受体复合时，通过考虑配体环（或实际上其它体积大的刚性配体结构）在配体上的状态环境，可以显着改善评分功能。 在其最通用形式中，本发明的特征在于定量配体和受体分子之间的结合亲和力的特定组分。 具体来说，当配体与受体分子结合时，所讨论的组分考虑了配体环结构（或体积大的刚性配体结构）及其周围环境之间的空间关系。 当量化单独反映这些特定配体特征的组分时，可以使用方法步骤，或者步骤可以是量化结合亲和力的全面方法的一部分，其包括与组分相关的结合亲和力相关的许多其它因子。 例如，可以计算初始结合亲和力，然后基于环结构的分类至少部分获得的因子来调整初始结合亲和力。

公开(公告)号：US20120303292A1

公开(公告)日：2012-11-29

申请号：US13113506

申请日：2011-05-23

申请人： Richard A. Friesner ,  Robert Murphy

发明人： Richard A. Friesner ,  Robert Murphy

IPC分类号： G06F19/00

CPC分类号： G06F19/706

摘要： A method of scoring binding affinity of a proposed ligand molecule for a receptor molecule using computer analysis and computer data bases to accounts for the increase in energy required where docking disrupts or partially disrupts the π-conjugated character of the ligand when bound to the receptor. The method uses data representing one or more proposed ligand molecules to be scored and data representing the receptor molecule. Computer analysis of the proposed ligand molecule data determines whether the ligand includes at least one π-conjugated moiety having multiple possible geometries, one of those geometries being characterized by less delocalization of electrons across the π-conjugated moiety than the delocalization of electrons characterizing another of those geometries. Computer analysis of the predicted ligand-receptor structure determines whether the ligand in the ligand-receptor structure adopts the geometry characterized by less delocalization. If so, a penalty is explicitly imposed for reduced delocalization of electrons across the π-conjugated moieties.

摘要翻译： 使用计算机分析和计算机数据库对拟议的配体分子对受体分子的结合亲和力进行评估的方法，以考虑到所需能量的增加所需的能量的增加，其中对接在与受体结合时破坏或部分地破坏配体的共轭特征 。 该方法使用表示一个或多个所提出的配体分子得分的数据和表示受体分子的数据。 所提出的配体分子数据的计算机分析确定配体是否包括具有多个可能几何形状的至少一个共轭部分，其中一个几何的特征在于电子跨越π-共轭部分的离域远离局部化 另一个这些几何。 预测的配体 - 受体结构的计算机分析确定配体 - 受体结构中的配体是否采用以较少离域为特征的几何。 如果是这样的话，明确规定减少电子跨越π-共轭部分的局域化的惩罚。