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1. 发明授权

US10424398B2 Method for aligning molecules in three dimensions based upon their correspondence to an exemplary template molecule for use in performing 3D QSAR analyses 有权
公开(公告)号：US10424398B2
公开(公告)日：2019-09-24
申请号：US14337832
申请日：2014-07-22
申请人： Richard D. Cramer
发明人： Richard D. Cramer
IPC分类号： G16C20/50
摘要： A computerized procedure for aligning molecules for use in CoMFA or other 3D QSAR methodologies does not rely on fragmentation of the molecules instead, aligning molecules based upon comparison to identified template molecules. Initially an anchor bond is identified in the candidate and template molecule that have similar atoms at each end of the bonds. The anchor bond need not be an acyclic bond. The candidate molecule is overlaid onto the template molecule by aligning the anchor bonds. Starting and working away from the anchor bond, matching atoms or atom types between the candidate and template molecule are identified. Once all matching atoms have been identified, the 3D coordinates of the template atoms are assigned to the corresponding atoms in the candidate molecule to place the candidate molecule into alignment.

2. 发明授权

US08504302B2 Template constrained fragment alignment used to identify fragments of similar shape and activity in drug development 有权
标题翻译：用于识别药物开发中类似形状和活性的片段的模板约束片段比对
公开(公告)号：US08504302B2
公开(公告)日：2013-08-06
申请号：US13018195
申请日：2011-01-31
申请人： Richard D. Cramer
发明人： Richard D. Cramer
IPC分类号： G06F19/00 , G01N31/00 , G06G7/58
CPC分类号： G06F19/706
摘要： The computational drug discovery method disclosed herein permits a user to specify a three dimensional representation of a molecular fragment derived from a query molecule involved in a drug interaction that then serves as a template to which fragments derived from molecules in database libraries may be aligned. The likely activity of the substitution of the fragment from the database library for the fragment from the query molecule may then be predicted by appropriate shape characterization and CoMFA analysis. The spatial three dimensional representation of the query fragment may be developed from binding data, crystallographic data, modeling data, or any other biophysical or biochemical technique.
摘要翻译：本文公开的计算药物发现方法允许用户指定衍生自参与药物相互作用的查询分子的分子片段的三维表示，其然后用作模板，来自数据库文库中的分子的片段可以与其对齐。然后可以通过适当的形状表征和CoMFA分析来预测来自查询分子的来自数据库库的片段的可能活性。查询片段的空间三维表示可以从结合数据，晶体学数据，建模数据或任何其他生物物理或生物化学技术开发。

3. 发明授权

US07184893B2 Method for selecting an optimally diverse library of small molecules based on validated molecular structural descriptors 有权
标题翻译：基于经验证的分子结构描述符选择小分子的最佳多样文库的方法
公开(公告)号：US07184893B2
公开(公告)日：2007-02-27
申请号：US09776708
申请日：2001-02-05
申请人： Richard D. Cramer , Robert D. Clark
发明人： Richard D. Cramer , Robert D. Clark
IPC分类号： G01N33/48 , G06F7/00 , G06G7/48
CPC分类号： C40B50/02 , B01J2219/007 , C40B30/02 , G06F19/704 , Y10S707/99943
摘要： The use for biological screening purposes of a subset (library) of a large combinatorially accessible chemical universe increases the efficiency of the screening process only if the subset contains members representative of the total diversity of the universe. In order to insure inclusion in the subset of molecules representing the total diversity of the universe under consideration, valid molecular descriptors which quantitatively reflect the diversity of the molecules in the universe are required. A unique validation method is used to examine both a new three dimensional steric metric and some prior art metrics. With this method, the relative usefulness/validity of individual metrics can be ascertained from their application to randomly selected literature data sets. By the appropriate application of validated metrics, the method of this invention selects a subset of a combinatorial accessible chemical universe such that the molecules of the subset are representative of all the diversity present in the universe and yet do not contain multiple members which represent the same diversity (oversample). The use of the neighborhood definition of a validated metric may also be used to combine (without oversampling the same diversity) any number of combinatorial screening libraries.
摘要翻译：用于大型组合可访问化学宇宙的子集（库）的生物筛选目的仅在子集包含代表宇宙总体多样性的成员时提高筛选过程的效率。为了确保包含在表示所考虑的宇宙总体多样性的分子子集中，需要定量反映宇宙中分子多样性的有效分子描述符。一种独特的验证方法用于检查新的三维空间度量和一些现有技术的度量。使用这种方法，可以从其应用于随机选择的文献数据集中确定各个度量的相对有用性/有效性。通过适当应用经验证的度量，本发明的方法选择组合可访问化学宇宙的子集，使得该子集的分子代表存在于宇宙中的所有分集，但不包含表示相同的多个成员多样性（过度抽样）。使用验证度量的邻域定义也可以用于组合（不过采样相同的多样性）任意数量的组合筛选库。

4. 发明申请

US20080172216A1 Forward synthetic synthon generation and its useto identify molecules similar in 3 dimensional shape to pharmaceutical lead compounds 有权
标题翻译：正向合成合成子的产生及其用途，将三维形状的分子识别为药物铅化合物
公开(公告)号：US20080172216A1
公开(公告)日：2008-07-17
申请号：US11728727
申请日：2007-03-26
申请人： Richard D. Cramer , Robert Jilek
发明人： Richard D. Cramer , Robert Jilek
IPC分类号： G06G7/58
CPC分类号： G06F19/706 , G06F19/702 , G06F19/705
摘要： A forward synthetic method is described that utilizes recursive application of established organic chemical reactions to derive more complex synthons from available reagents than are available from the reagent synthons themselves. The product of each reaction serves as the starting point for further reactions thereby permitting the generation of multiple complex molecular structures. This synthon generation procedure typically yields 20 ? 30 new structures within the limits of easily accessible syntheses based upon each starting reagent. More complex syntheses yield even more structures. The generated synthons are characterized with a molecular structural descriptor possessing a neighborhood property and can be further characterized with features. The synthons are searched for three dimensional shape and feature similarity to molecular fragments derived from query molecules, typically pharmacological molecules of interest. Identified synthons can be assembled into molecules possessing the same three dimensional shape and likely activity as the molecule of interest.
摘要翻译：描述了正向合成方法，其利用已建立的有机化学反应的递归应用以从可用的试剂得到比可从试剂合成器本身得到的更复杂的合成子。每个反应的产物作为进一步反应的起始点，从而允许产生多个复合分子结构。这个合成子生成过程通常产生20？基于每种起始试剂，容易获得的合成范围内的30种新结构。更复杂的合成产生更多的结构。生成的合成子的特征在于具有邻域性质的分子结构描述符，并且可以进一步用特征进行表征。搜索合成子的三维形状，并且与来自查询分子（通常是目的药理学分子）的分子片段相似。识别的合成子可以组装成具有与感兴趣的分子相同的三维形状和可能的活性的分子。

5. 发明授权

US07330793B2 Method for searching heterogeneous compound databases using topomeric shape descriptors and pharmacophoric features 有权
标题翻译：使用顶点形状描述符和药效特征搜索异质复合数据库的方法
公开(公告)号：US07330793B2
公开(公告)日：2008-02-12
申请号：US09825448
申请日：2001-04-02
申请人： Richard D. Cramer , Robert J. Jilek , Qian Liu , Stephan Guessregen , Bernd Wendt , Katherine M. Andrews
发明人： Richard D. Cramer , Robert J. Jilek , Qian Liu , Stephan Guessregen , Bernd Wendt , Katherine M. Andrews
IPC分类号： G01N33/48
CPC分类号： C40B30/02
摘要： Heterogeneous compound databases can be searched for compounds which are likely to have the same biological activity as a known (query) molecule. Query molecules and the molecules in the database are split into fragments according to common fragmentation rules. Fragments are aligned in a uniform conformation according to a topomeric alignment process and interaction energy fields, typically steric fields, between a probe and the fragment atoms are generated to capture the fragment shapes. Comparison of the fields for the query fragments with the fields for the database compound fragments yields a measure of shape similarity. Searches for similarly shaped substructures and cores can also be readily accomplished. Pharmacophoric style features can be defined for the topomerically aligned fragments but with user specified weighting of the importance of each. Differences in features are defined with the same dimensionality as shape so that both shape and features can be used to search.
摘要翻译：可以搜索可能与已知（查询）分子具有相同生物活性的化合物的异质化合物数据库。查询分子和数据库中的分子根据常见的碎片规则分为片段。根据顶点对准方法将片段按均匀构象排列，生成探针和片段原子之间的相互作用能场（通常为空间场）以捕获片段形状。将查询片段的字段与数据库化合物片段的字段进行比较可以产生形状相似度的度量。类似形状的子结构和芯的搜索也可以容易地实现。可以为顶点对齐的片段定义药典风格特征，但用户可以对每个片段的重要性给予指定的权重。特征的差异以与形状相同的维度定义，使得形状和特征都可以用于搜索。

6. 发明授权

US3932455A Carbazole phthaleins 失效
标题翻译：咔唑phthaleins
公开(公告)号：US3932455A
公开(公告)日：1976-01-13
申请号：US472162
申请日：1974-05-22
申请人： Ruth C. Bilofsky , Richard D. Cramer
发明人： Ruth C. Bilofsky , Richard D. Cramer
IPC分类号： G03C8/48 , C07D209/86
CPC分类号： G03C8/48
摘要： This invention relates to a new class of indicator dyes useful as optical filter agents in photographic processes to protect a selectively exposed photosensitive material from further exposure during processing in the presence of incident light. Such dyes comprise 3,6-disubstituted carbazoles wherein the 3,6 substituents are selected from a phthalidyl radical, C.sub.6 H.sub.4.CO.O.CR--, wherein R is an aryl group and an o-carboxybenzoyl radical, not more than one of said substituents being o-carboxybenzoyl.
摘要翻译：本发明涉及一种新型的指示剂染料，其可用作照相工艺中的光学过滤剂，以在入射光的存在下保护选择性曝光的感光材料免于进一步曝光。这样的染料包括3,6-二取代的咔唑，其中3,6个取代基选自酞菁基C6H4CO.O.CR-，其中R是芳基和邻羧基苯甲酰基，不超过一个所述取代基是邻羧基苯甲酰基。

7. 发明授权

US07860657B2 Forward synthetic synthon generation and its useto identify molecules similar in 3 dimensional shape to pharmaceutical lead compounds 有权
标题翻译：正向合成合成子的产生及其用途，将三维形状的分子识别为药物铅化合物
公开(公告)号：US07860657B2
公开(公告)日：2010-12-28
申请号：US11728727
申请日：2007-03-26
申请人： Richard D. Cramer , Robert Jilek
发明人： Richard D. Cramer , Robert Jilek
IPC分类号： G06F7/00
CPC分类号： G06F19/706 , G06F19/702 , G06F19/705
摘要： A forward synthetic method is described that utilizes recursive application of established organic chemical reactions to derive more complex synthons from available reagents than are available from the reagent synthons themselves. The product of each reaction serves as the starting point for further reactions thereby permitting the generation of multiple complex molecular structures. This synthon generation procedure typically yields 20 ? 30 new structures within the limits of easily accessible syntheses based upon each starting reagent. More complex syntheses yield even more structures. The generated synthons are characterized with a molecular structural descriptor possessing a neighborhood property and can be further characterized with features. The synthons are searched for three dimensional shape and feature similarity to molecular fragments derived from query molecules, typically pharmacological molecules of interest. Identified synthons can be assembled into molecules possessing the same three dimensional shape and likely activity as the molecule of interest.
摘要翻译：描述了正向合成方法，其利用已建立的有机化学反应的递归应用以从可用的试剂得到比可从试剂合成器本身得到的更复杂的合成子。每个反应的产物作为进一步反应的起始点，从而允许产生多个复合分子结构。这个合成子生成过程通常产生20？基于每种起始试剂，容易获得的合成范围内的30种新结构。更复杂的合成产生更多的结构。生成的合成子的特征在于具有邻域性质的分子结构描述符，并且可以进一步用特征进行表征。搜索合成子的三维形状，并且与来自查询分子（通常是目的药理学分子）的分子片段相似。识别的合成子可以组装成具有与感兴趣的分子相同的三维形状和可能的活性的分子。

8. 发明申请

US20090228463A1 Method for Searching Compound Databases Using Topomeric Shape Descriptors and Pharmacophoric Features Identified by a Comparative Molecular Field Analysis (CoMFA) Utilizing Topomeric Alignment of Molecular Fragments 审中-公开
标题翻译：使用拓扑形状描述符和通过比较分子场分析（CoMFA）识别的化合物数据库的方法利用分子片段的拓扑定位
公开(公告)号：US20090228463A1
公开(公告)日：2009-09-10
申请号：US12045511
申请日：2008-03-10
申请人： Richard D. Cramer , Brian Campbell
发明人： Richard D. Cramer , Brian Campbell
IPC分类号： G06F7/06 , G06F17/30
CPC分类号： G16C20/40 , G16C20/30
摘要： A CoMFA 3D QSAR shape analysis may be performed on molecules arising from the same activity series that may be decomposed/viewed as assemblies of discrete identifiable subunits. The disclosed method provides for identifying in databases of whole molecules those molecular subunits that possess the same shape or shape and feature characteristics as the subunits of molecules used to perform the CoMFA analysis. Additionally, the method provides for estimation of the likely biological activity of molecules assembled from the subunits identified in the molecular database.
摘要翻译：可以对可能被分解/视为离散可识别亚基的组合的相同活性序列产生的分子进行CoMFA 3D QSAR形状分析。所公开的方法提供了在整个分子的数据库中鉴定具有与用于进行CoMFA分析的分子的亚基相同的形状或形状和特征特征的分子亚基。此外，该方法提供了从分子数据库中鉴定的亚基组装的分子的可能生物活性的估计。

9. 发明授权

US07329222B2 Comparative field analysis (CoMFA) utilizing topomeric alignment of molecular fragments 有权
标题翻译：比较场分析（CoMFA）利用分子片段的顶点取向
公开(公告)号：US07329222B2
公开(公告)日：2008-02-12
申请号：US10374741
申请日：2003-02-25
申请人： Richard D. Cramer , Robert Jilek
发明人： Richard D. Cramer , Robert Jilek
IPC分类号： C40B30/02 , G06F19/00 , G01N31/00
CPC分类号： G06F19/704 , C40B30/02
摘要： The static and electrostatic interaction energy fields between probe atoms and the atoms of a topomerically aligned fragment placed in a three-dimensional grid may be used to derive a CoMFA model. The topomeric CoMFA model coefficients may be used to predict partial activity values for fragments not derived from molecules of the activity series. The partial activities can be summed to provide a predicted activity for all fragment positions of the activity series molecules. A Virtual Library in which topomerically aligned fragments are associated with their respective steric and electrostatic interaction energies can be searched for fragments similar in shape to the fragments derived from the molecules of the activity series. The identified fragments can be used with the topomeric CoMFA coefficients to predict their activity if used in the molecular activity series.
摘要翻译：探针原子与放置在三维网格中的顶点对准片段的原子之间的静态和静电相互作用能场可用于导出CoMFA模型。可以使用顶点CoMFA模型系数来预测不是源于活动序列分子的片段的部分活性值。可以将部分活性相加以提供活性序列分子的所有片段位置的预测活性。可以搜索其中与其各自的空间和静电相互作用能量相关联的端基对齐片段的虚拟文库，其形式与从活性序列分子得到的片段相似。如果在分子活性序列中使用，所识别的片段可以与拓扑结构的CoMFA系数一起用于预测它们的活性。

10. 发明授权

US07136758B2 Virtual library searchable for possible combinatorially derived product molecules having desired properties without the necessity of generating product structures 失效
标题翻译：虚拟库可以搜索具有所需性质的可能的组合衍生产物分子，而不需要产生产物结构
公开(公告)号：US07136758B2
公开(公告)日：2006-11-14
申请号：US09866543
申请日：2001-05-25
申请人： David E. Patterson , Richard D. Cramer
发明人： David E. Patterson , Richard D. Cramer
IPC分类号： G01N33/48 , G06F7/48
CPC分类号： C40B30/02 , B01J2219/007 , C40B50/02 , G06F19/704 , Y10S707/99943
摘要： The problem of how to select out of a large chemically accessible universe molecules representative of the diversity of that universe is resolved by the discovery of a method to validate molecular structural descriptors. Using the validated descriptors, optimally diverse subsets can be selected. In addition, from the universe, molecules with characteristics similar to a selected molecule can be identified. The validated descriptors also enable the generation of a huge virtual library of potential product molecules which could be formed by combinatorial arrangement of structural variations and cores. In this virtual library it is possible to search billions of possible product compounds in relatively short time frames.
摘要翻译：通过发现一种验证分子结构描述符的方法来解决如何选择代表宇宙多样性的大型化学可及性宇宙分子的问题。使用经过验证的描述符，可以选择最佳多样化的子集。此外，从宇宙中，可以鉴定具有与选定分子相似的特征的分子。经验证的描述符还可以生成潜在产品分子的巨大虚拟库，这些潜在的产品分子可以通过结构变化和核心的组合布置形成。在这个虚拟库中，可以在相对较短的时间范围内搜索数十亿种可能的产品化合物。

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