3DFs:用于药物设计的三维结构柔性搜索系统

在三维结构数据库中搜索含有某种药效团的分子的三维结构搜索法已经成为新药研制的重要手段，近年已有了广泛的发展。３ＤＦＳ是我室研制的用于药物分子设计的三维结构柔性搜索系统，该系统支持由化学功能基团定义的药效团，并详细定义了氢键给体、氢键受体、电荷中心、疏水区等重要化学功能基团的结构类型，并且具有三维构象柔性搜索功能。     

基于药效团的三维数据库搜索

用表皮生长因子受体酪氨酸激酶抑制剂的药效团作为提问结构在三维数据库中进行了搜索.从得到的命中结构中挑选了12个化合物用柔性受体模型方法对其活性进行了预测, 发现有2个化合物具有一定的预测活性.这2个化合物可能具有酪氨酸激酶抑制剂的活性, 可能作为先导化合物进行结构优化.     

含过渡金属和柔性配体催化体系的构象搜索

采用密度泛函理论对含有过渡金属和柔性配体的分子进行优化时,通常只能将初始结构优化到势能面上的局部最小点,而确定反应势能面上各中间体和过渡态的最低能量构象是准确描述一个催化反应最优路径的关键.使用Cr/PCCP体系催化乙烯选择性三聚/四聚反应路径中的关键过渡态(TS1,TS2,TS3)作为分子模型,对基于Tinker软件包和CREST软件包的两种构象搜索方法进行了对比测试.使用两种构象搜索方法均成功找到了三个分子模型的最低能量构象,并且两种方法获得的构象数量总数相差不大.与基于Tinker软件包的构象搜索方法相比,使用CREST软件包进行构象搜索的计算流程更加简单,并且大大减少了计算时间.     

光系统Ⅱ抑制剂—反式氰基丙烯酸酯比较分子场和电子结构研究

对反式氰基丙烯酸酯系列活性分子采用限制性系统搜索方法确定的药效团模型 ,与 9类不同骨架结构的光系统 抑制剂 DISCO模型中的反式氰基丙烯酸酯分子(M- 2 2 )的活性构象为模板所确定的药效团模型是非常相近的。对两种方法所获得的活性构象分子进行了 Co MFA研究 ,其结果是一致的。采用 PM3方法进行了量子化学计算 ,计算结果表明两种模型的构象分子具有相近的电子结构 ,根据分子静电场、立体场和电子结构探讨了该类抑制剂的构效关系。     

咪唑啉酮类除草剂的三维构效关系研究

从三维角度出发,采取不同的构象搜索方法得到了咪唑酮类化合物分子的活性构象。利用比较分子场分析方法进一步证实了模板分子构象的正确性。并从静电场、立体场及活性关系等方面进行了三维定量构效关系研究,得到了具有较强预测能力的QSAR模型。     

距离比较法构建M1受体激动剂药效团模型

在M1受体三维结构未知的情况下,利用距离比较法(DISCO)对24个具有Mi受体激动活性的化合物进行了研究,构建了Mi受体激动剂可能的药效团模型,为设计新M1受体激动剂提供了参考,并以此为提问结构在ACD数据库和中草药数据系统(TCMDB)中进行搜索,得到一系列结构新颖并可能具有Mi激动活性的化合物.     

距离比较法构建M1受体激动剂药效团模型

在M1受体三维结构未知的情况下,利用距离比较法（DISCO）对24个具有M1受体激动活性的化合物进行了研究,构建了M1受体激动剂可能的药效团模型,为设计新M1受体激动剂提供了参考,并以此为提问结构在ACD数据库和中草药数据系统（TCMDB）中进行搜索,得到一系列结构新颖并可能具有M1激动活性的化合物.     

自动化势能面搜索方法新进展

本文简要介绍了势能面搜索的两个主要问题,即过渡态搜索和全局势能面搜索,并针对这两个问题介绍了本研究组最近发展的3种方法,即限制最小化双子算法、偏置势函数辅助限制性最小化双子算法以及势能面随机行走方法．这3种方法均只需计算一阶梯度,能够用于快速自动化的搜索过渡态以及势能面．通过几个典型例子分别说明了3种方法的特点及优势．     

去B链羧端七肽胰岛素晶体结构的测定

去B链羧端七肽胰岛素(DHPI)晶体中不对称单位合二个分子,空间群P2_12_12_1。运用Patterson搜索技术确定了二个分子在晶胞中的取向,联合运用平移函数和R因子搜索测定了两个分子各自在晶胞中的位置。运用生物大分子刚体最小二乘修正技术和能量极小化最小二乘制约修正精化分子的取向和位置后,在6分辨率晶体学R因子下降到0.384。初始Fourier图显示,与天然胰岛素分子相较,DHPI分子的B链N端(B1—B8)和C端(B20—B23)肽段的构象有剧列变化,但A,B链的三段螺旋及其相对配置大体保持。     

计算机辅助分子设计的三维结构搜寻方法

三维结构搜寻是一种新型的计算机辅助分子设计方法。本文对表征三维结构的信息来源、三维结构搜寻基本方法及其在药物分子设计中的应用作了较系统的综述，它不仅可用于先导化合物的优化，更重要的是有用于新型先导化合物的发展。此外，它也可用于新型农用化学品、材料、催化剂和聚合物的开发。     

Similarity searching in files of three-dimensional chemical structures: Representation and searching of molecular electrostatic potentials using field-graphs

This paper reports a method for the identification of those molecules in a database of rigid 3D structures with molecular electrostatic potential (MEP) grids that are most similar to that of a user-defined target molecule. The most important features of an MEP grid are encoded in field-graphs, and a target molecule is matched against a database molecule by a comparison of the corresponding field-graphs. The matching is effected using a maximal common subgraph isomorphism algorithm, which provides an alignment of the target molecule's field- graph with those of each of the database molecules in turn. These alignments are used in the second stage of the search algorithm to calculate the intermolecular MEP similarities. Several different ways of generating field-graphs are evaluated, in terms of the effectiveness of the resulting similarity measures and of the associated computational costs. The most appropriate procedure has been implemented in an operational system that searches a corporate database, containing ca. 173,000 3D structures.     

An inequality for 3D database searching and its use in evaluating the treatment of conformational flexibility

Summary A mathematical formula is introduced for predicting the number of hits that should be observed in a flexible 3D database search, based on the results of a set of related queries. The projected number of hits is always greater than or equal to the actual number of hits, the discrepancy being due to imperfect treatment of conformational flexibility of the molecules. Hence, the difference between the projected and actual number of hits, , serves to measure how well conformational flexibility is being treated, in a manner that is objective, easy for a user to quickly verify, and independent of the particular algorithm for flexible 3D database search. It is shown that is a function both of how well conformational flexibility is treated and of the precision of the query. When the distance constraint is defined only to a precision of ±2.0 Å, in a single-conformer database of drug-like molecules values of only 0.03 are found, while in a single-conformer database of di- and tripeptides, is 0.15. At increased precision, a flexible 3D database search becomes critical. For a single-conformer database, using a query of precision ±0.2 Å, applied to a database of drug-like molecules, is 0.97; applied to a database of di- and tripeptides, is 2.21. By contrast, treating conformational flexibility by storing up to 100 conformers per molecule, at this precision, applied to a database of drug-like molecules, is 0.002; applied to a database of di- and tripeptides, is 0.07. This inequality, and hence , is defined only for database queries containing a single distance constraint; how the inequality may generalize to higher-dimensional queries is still unclear.     

A hybrid approach for addressing ring flexibility in 3D database searching

A hybrid approach for flexible 3D database searching is presented that addresses the problemof ring flexibility. It combines the explicit storage of up to 25 multiple conformations ofrings, with up to eight atoms, generated by the 3D structure generator CORINA with thepower of a torsional fitting technique implemented in the 3D database system UNITY. Acomparison with the original UNITY approach, using a database with about 130,000 entriesand five different pharmacophore queries, was performed. The hybrid approach scored, on anaverage, 10–20% more hits than the reference run. Moreover, specific problems withunrealistic hit geometries produced by the original approach can be excluded. In addition, theinfluence of the maximum number of ring conformations per molecule was investigated. Anoptimal number of 10 conformations per molecule is recommended.     

DBMAKER: A set of programs to generate three-dimensional databases based upon user-specified criteria

Summary DBMAKER is a program that, in conjunction with CONCORD, generates three-dimensional structural databases. Numerous user-defined parameters monitor content, composition, size and connectivity information, but allow the program to generate random compounds within the scope of these constraints. SMILES string representations are generated, and conversion to 3D is performed by CONCORD. This assures high-quality 3D structures and portability to numerous proprietary storage formats. Methods are described to maintain compound registration, allowing database expansion as required without duplication.     

CAVEAT: A program to facilitate the design of organic molecules

Summary A frequently encountered problem in the design of enzyme inhibitors and other biologically active molecules is the identification of molecular frameworks to serve as templates or linking units that can position functional groups in specific relative orientations. The program CAVEAT was designed to address this problem by searching 3D databases for such molecular fragments. Key innovations introduced in CAVEAT are a focus on relationships between bonds and the provision of automated methods to identify and classify structural frameworks. Performance has been a particular concern in formulating CAVEAT, since it is intended to be used in an interactive manner. The focus in this report is the design and implementation of the principal algorthms and the performance achieved.CAVEAT is available from the Office of Technology Licensing, University of California, Berkeley, CA, and from Molecular Simulations, Inc., Burlington, MA; further information is available from P.A. Bartlett.     

The discovery of novel auxin transport inhibitors by molecular modeling and three-dimensional pattern analysis

Summary Molecular modeling techniques and three-dimensional (3D) pattern analysis have been used to investigate the chemical and steric properties of compounds that inhibit transport of the plant hormone auxin. These compounds bind to a specific site on the plant plasma membrane characterized by its affinity for the herbicide N-1-naphthylphthalamic acid (NPA). A 3D model was derived from critical features of a set of ligands for the NPA receptor, a suggested binding conformation is proposed, and implications for the topographical features of the NPA receptor are discussed. This model, along with 3D structural analysis techniques, was then used to search the Abbott corporate database of chemical structures. Of the 467 compounds that satisfied the criteria of the model, 77 representative molecules were evaluated for their ability to compete for the binding of [³H]NPA to corn microsomal membranes. Nineteen showed activity that ranged from 16 to 85% of the maximum NPA binding. Four of the most active of these, representing chemical classes not included in the original compound set, were also found to inhibit polar auxin transport through corn coleoptile sections. Thus, this study demonstrates that 3D analysis techniques can identify active, novel ligands for biochemical target sites with concomitant physiological activity.     

SPLICE: A program to assemble partial query solutions from three-dimensional database searches into novel ligands

Summary SPLICE is a program that processes partial query solutions retrieved from 3D, structural databases to generate novel, aggregate ligands. It is designed to interface with the database searching program FOUNDATION, which retrieves fragments containing any combination of a user-specified minimum number of matching query elements. SPLICE eliminates aspects of structures that are physically incapable of binding within the active site. Then, a systematic rule-based procedure is performed upon the remaining fragments to ensure receptor complementarity. All modifications are automated and remain transparent to the user. Ligands are then assembled by linking components into composite structures through overlapping bonds. As a control experiment, FOUNDATION and SPLICE were used to reconstruct a know HIV-1 protease inhibitor after it had been fragmented, reoriented, and added to a sham database of fifty different small molecules. To illustrate the capabilities of this program, a 3D search query containing the pharmacophoric elements of an aspartic proteinase-inhibitor crystal complex was searched using FOUNDATION against a subset of the Cambridge Structural Database. One hundred thirty-one compounds were retrieved, each containing any combination of at least four query elements. Compounds were automatically screened and edited for receptor complementarity. Numerous combinations of fragments were discovered that could be linked to form novel structures, containing a greater number of pharmacophoric elements than any single retrieved fragment.