Synthetically Accessible Virtual Inventory (SAVI)

SAVI项目基于：(A)一套带有丰富化学上下文注释的转换，包括官能团反应性数据(美国拉萨，LLC；和英国拉萨有限公司)(B)一套高度注释的构建块(Sigma-Aldrich，全球战略服务)(C)带有定制开发的化学信息学工具包CACTVS(德国)。转换是一套以CHMTRN/Patran语言描述的1,500多条规则，用于编码化学转换，添加了化学上下文和质量标准，最终基于E.J.Corey的开创性工作。与简单的傻笑变换相比，这些规则允许/提供：-根据目标的整体结构特征，计算反应是否会起作用。-评分：如果反应奏效，考虑到整体结构特征，反应有多稳健。-是否需要对干扰组进行保护-然后可以将这些内容整合到最终的起始材料查询中，以确定预先保护的起始材料的优先顺序。-提出适当的上下文相关反应条件。-特定情况下的文本警告，例如多个产品的可能性、边界条件等。规则的辅助信息是一组官能团反应性数据，即描述规则集中的任何标准官能团在任何标准条件下是否不稳定的表格。积木是一组数十万克数量的化合物，具有很高的可靠性，来自或通过Sigma-Aldrich。此集合已使用定价信息和其他对此项目有用的商业智能类型数据进行了注释。化学信息学工具包CACTVS已以各种方式扩展，例如具有读取CHMTRN/Patran转换的能力。需要实施的一个重要特点是，对于严格的正演合成SAVI项目，在不重写规则的情况下，处理原有拉萨变换方向的逆转。另一个重要功能是初始和最终起始材料(SM)查询处理，即4步：从规则中的2D模式提取初始SM查询；从2D模式正向反应；评分(这是拉萨唯一的原始功能)；最终SM查询扩展(R组、保护组等)。为了在药物开发上下文中过滤掉具有不太期望的属性的结构的目标，已经实现了在当前药物设计中被认为重要的几个附加的计算属性，例如由Bruns和Watson(J.Med.化学。2012年，55.9763.9772)；dx.doi.org/10.1021/jm301008n.在这个项目目前非常早期的阿尔法阶段，只使用了可能的1,500个转换中的11个；应用到大约。230,000块积木；只需一步反应。得到的610,000个产物已经被注释，但还没有用任何计算的或相关的分子性质进行过滤。为了限制文件大小，仅对理论上可能的产物(一步反应)的百分之一左右进行了采样。我们已经解决了生成转换的示意性图形表示的任务。我们的最终目标是创建一个包含10亿个高质量筛选样本的数据库，这些样本应该可以轻松且廉价地合成。我们的第一次全面生产，使用了14个转换和大约377,000个构建块，已经产生了超过2.36亿件产品。这些新的分子都用一条建议的简单和高产率的合成路线以及我们已经实施的在尖端药物设计中被公认为重要的50种分子性质来注释。计划建立一个网络图形用户界面，允许用户通过包括子结构搜索在内的各种标准的搜索来自由访问该数据库。它还将提供指向页面的链接，用户可以在这些页面上提出由商业实体合成分子(S)的请求。到目前为止还没有在知识库中对化学进行的其他新颖的转换已经编写完成，并正在进行测试，为下一次全面生产做准备。

The SAVI Project is based on: (a) a set of transforms with rich chemical context annotation including functional group reactivity data (LHASA, LLC, U.S.; and Lhasa Limited, UK) (b) a set of highly annotated building blocks (Sigma-Aldrich, Global Strategic Services) (c) the chemoinformatics toolkit CACTVS with custom development (Xemistry GmbH, Germany) The transforms are a set of more than 1,500 rules described in the CHMTRN/PATRAN language for encoding chemical transformations with chemical context and quality criteria added, based ultimately on the pioneering work of E. J. Corey. These rules, in contrast to simple SMIRKS transforms, allow/provide: - Computation of whether a reaction, depending on the overall structural features of the target, will work at all. - Scoring: If the reaction works, how robust it is, taking into account overall structural features. - Whether protection of interfering groups is required - and these can then already be integrated in the final starting materials queries to prioritize pre-protected starting materials. - Proposal of suitable context-dependent reaction conditions. - Textual warnings in specific circumstances, such as potential of multiple products, borderline conditions, etc. Ancillary information to the rules is a set of functional group reactivity data, i.e. a table describing whether any of the standard functional groups in the rule set is unstable under any of the standard conditions. The building blocks are a set of several hundred thousand compounds available in gram quantities, and with high reliability, from, or through, Sigma-Aldrich. This set has been annotated with pricing information and other business intelligence type data useful for this project. The chemoinformatics toolkit CACTVS has been expanded in various ways, e.g. with the capability to read the CHMTRN/PATRAN transforms. An important feature that needed to be implemented was the handling of the reversal of the original LHASA transform direction, without re-writing rules, for the strictly forward-synthetic SAVI project. Another important capability was the initial and final starting material (SM) query handling, i.e. the 4-steps: initial SM query extraction from the 2D patterns in the rules; forward reaction from the 2D patterns; scoring (which is the only original LHASA functionality); final SM query expansion (R-groups, protecting groups, etc.). For the goal of filtering out structures with less-than-desirable attributes in the drug development context, several additional computed properties regarded as important in current drug design have been implemented, such as the demerit scores based on 275 rules for identifying potentially reactive or promiscuous compounds, published by Bruns and Watson (J. Med. Chem. 2012, 55, 9763?9772); dx.doi.org/10.1021/jm301008n. In the current, very early alpha, stage of this project, only 11 transforms of the possible 1,500 were used; applied to approx. 230,000 building blocks; in only one-step reactions. The 610,000 resulting products have been annotated but not yet filtered with any of the computed or associated molecular properties. To limit the file size, only on the order of one percent of the theoretically possible products (of one-step reactions) was sampled. We have addressed the task of generating schematic graphical representations of the transforms. We are ultimately aiming at creating a database of one billion high-quality screening samples that should be easily and cheaply synthesizable. Our first full production run, using 14 transforms and about 377,000 building blocks, has resulted in more than 236 million products. These novel molecules are all annotated with a proposed simple and high-yield synthetic route, as well as by 50 molecular properties generally recognized as important in cutting-edge drug design that we have implemented. A web GUI is planned that will allow users free access to this database via searches by various criteria including substructure searches. It will also present links to pages where users can place requests for having the molecule(s) synthesized by commercial entities. Additional novel transforms for chemistry heretofore not in the knowledgebase have been written and are being tested in preparation for the next full production run.