Better Understanding and Handling of Tautomerism

因此，我们互变异构相关工作的一个动机是使用我们掌握的所有工具，化学信息学分析，QM计算，实验工作和从文献中系统提取结果，为如何改善InChI V2中互变异构处理的建议提供科学依据-而不仅仅是在工作组中进行投票。虽然质子移变互变异构规则是目前唯一在CACTVS中作为标准规则集实现的规则，并且InChI所涵盖的所有互变异构转换（默认或可选）都是质子移变的，但环-链（RC）互变异构是众所周知的和广泛的。然而，令人惊讶的是，直到最近，化学信息学中很少有RC规则。基于Baldwin提出的预测成环反应相对易度的规则，我们提出了一套共11条的RC互变异构规则。这些规则以SMIRKS线表示法编码，SMIRKS线表示法是化学结构线表示法SMILES的化学变换扩展，由Daylight Chemical Information Systems，Inc.开发，就像目前CACTVS中用于描述质子转移互变异构现象的20个独立规则被编码一样。对鲍德温的规则集进行了一些修改，毕竟，这些规则一般用于环闭合，而不是具体用于RC互变异构。最重要的是，涉及四面体亲电碳的闭环和开环反应，从而导致单键断裂，这将导致分子中原子的损失，违反互变异构的定义。将这些新的RC规则添加到CACTVS中现有的标准质子转移规则中，我们将此组合规则集应用于RC互变异构的“海报儿童”：华法林。这种抗凝血药物，广泛使用了几十年，理论上可以以40种不同的互变异构形式存在于溶液中。我们用计算方法（在B3 LYP/6- 311 G+水平上计算相对能量）研究了所有这些互变异构体，并记录了它们的NMR（13 C和1H）谱。我们介绍了一个直观的和图形化的网络互变异构体和它们的相互转换路径，其中华法林包含11个互变异构体和17个互变异构体之间的转换允许我们的规则。然后，我们将RC和亲质子性规则集应用于整个数据库：Aldrich Market Select（AMS）数据库（当时）有600万个筛选样本和构建模块。我们发现超过30，000个案例中，两种或两种以上的AMS产品被我们的规则宣布为同一化合物的不同互变异构形式。我们对从AMS购买的166个这样的互变异构体对（加上几个三联体）进行了1H和13 C NMR分析，以确定化学信息学转换是否准确地预测了与NMR确定的相同的“瓶中物质”。基本上，AMS中存在的所有质子转移转化的例子（一些“罕见”的互变异构类型在AMS中没有这样的“冲突对”）都得到了证实。一些RC变换被发现是太“侵略性”，即等同于彼此的结构，根据NMR分析是不同的化合物。这篇论文获得了化学信息与建模杂志的编辑选择。为了给互变异构相关的分析和化学信息学工作提供更多的实验数据，我们根据从实验文献中提取的数据创建了一个数据库。该数据库由1，873个条目组成，这些条目属于在一组特定实验条件（pH、溶剂、温度、技术）下研究的互变异构体的n-元组，由于n的平均值略为2，因此总计3，898条记录。这些数据是从73篇出版物中提取的，其中许多是综述，这些出版物是从提供给进行初始提取的承包商公司（Parthys Reverse Informatics）的200篇论文中挑选出来的，我们在文献检索中发现了大约900篇论文，其中可能包含有用的数据。每个互变异构体（或元组，视情况而定）用结构信息注释：SMILES、InChI、InChIKey、NCI/CADD标识符;“普遍性”数据：测量的比率、互变率、相对能量等;条件数据：溶剂、温度、pH值等（如果给出）;方法数据：NMR、UV光谱、IR光谱等;参考资料：书目资料。据我们所知，像互变异构体这样的数据库并不存在于其他地方，肯定不在公共领域。创建了一个新的Web服务-称为互变异构器-以应用和测试我们从上述数据库和文献中编译的转换，用于InChI（Key）V.2中互变异构处理的重新设计。同时，在这个项目的上下文中编译的转换集已经增长到最终的86个，它们也被添加到互变器中。IUPAC工作组已经开始启动并决定为InChI V2推荐的最终转换集。将86个rukes中的一些添加到当前InChI代码（v.1.05）中的探索性编码成功用于6个规则。基于量子力学计算和随后的深度学习方法的互变异构的第二级分析工作已经开始。此外，对上述小分子的子集进行了X射线晶体学分析。关于这个项目的几份手稿已经出版或正在编写中。

One motivation of our tautomerism-related work is thus to use all tools at our disposal, chemoinformatics analyses, QM computations, experimental work, and systematic extraction of results from literature, to provide a scientific footing for the recommendations how to improve handling of tautomerism in InChI V2 - instead of just holding a vote in the Working Group. While prototropic tautomerism rules are the only ones currently implemented as the standard rule set in CACTVS, and all tautomeric transformations covered by InChI (as default or by option) are prototropic, ring-chain (RC) tautomerism is well-known and widespread. Nevertheless, and somewhat surprisingly, very little in terms of RC rules was available in chemoinformatics until recently. Based on Baldwin's well-known set of rules to predict the relative facility of ring forming reactions, we developed a set of 11 rules describing RC tautomerism. The rules were encoded in SMIRKS line notation, the chemical transform extension of the chemical structure line notation SMILES, developed by Daylight Chemical Information Systems, Inc., just like the currently 20 individual rules in CACTVS for describing prototropic tautomerism are encoded. A number of modifications were applied to Baldwin's rule set, which, after all, were rules for ring-closure in general, not for RC tautomerism in specific. Foremost, ring closure and opening reactions involving a tetrahedral electrophilic carbon thus leading to breakage of a single bond would cause a loss of atoms to the molecule, violating the definition of tautomerism. Adding these new RC rules to the existing standard prototropic rules in CACTVS, we applied this combined rule set to the "poster child" of RC tautomerism: warfarin. This anticoagulant drug, in wide use for decades, can theoretically exist in solution in 40 distinct tautomeric forms. We investigated all these tautomers with computational approaches (relative energies calculated at the B3LYP/6-311G+ level of theory) and recorded NMR (13C and 1H) spectra. We introduced an intuitive and graphical network for tautomers and their interconversion paths, which for warfarin contained 11 tautomers and 17 tautomeric transformations between them allowed by our rules. We then applied the combined RC and prototropic rule set to an entire database: the Aldrich Market Select (AMS) database of (then) 6 million screening samples and building blocks. We found over 30,000 cases where two or more AMS products were declared by our rules to be just different tautomeric forms of the same compound. 1H and 13C NMR analysis of 166 such tautomer pairs (plus a few triplets) we purchased from the AMS were performed to determine whether the chemoinformatics transforms had accurately predicted what was the same "stuff in the bottle" as determined by NMR. Essentially all prototropic transforms for which examples in the AMS existed (some of the "rarer" types of tautomerism had no such "conflict pairs" in the AMS) were confirmed. Some of the RC transforms were found to be too "aggressive", i.e. to equate structures with one another that were different compounds according to the NMR analyses. This paper received an Editor's Choice selection in the Journal of Chemical Information and Modeling. In order to provide additional experimental data for tautomerism-related analyses and chemoinformatics work, we have created a database based on data extracted from experimental literature. This database consists of 1,873 entries which belong to n-tuples of tautomers studied in a particular set of experimental conditions (pH, solvent, temperature, technique), adding up to 3,898 records since the average of n is slightly 2. The data were extracted from 73 publications, many of them reviews, taken from a selection of 200 papers provided to the contractor company that did the initial extraction (Parthys Reverse Informatics), out of about 900 papers we identified in literature searches that might contain useful data for this purpose. Each tautomer (or tuple, as appropriate) is annotated with Structural information: SMILES, InChI, InChIKey, NCI/CADD Identifiers; "Prevalence" data: measured ratios, interconversion rates, relative energies etc.; Condition data: solvent, temperature, pH etc. (if given); Method data: NMR, UV spectroscopy, IR spectroscopy etc.; Reference data: Bibliographic information. To the best of our knowledge, such as tautomer database does not exist elsewhere, certainly not in the public domain. A new web service - called Tautomerizer - was created to apply and test the transforms we have compiled from the above database and literature for the Redesign of Handling of Tautomerism in InChI(Key) V.2. The set of transforms compiled in the context of this project has meanwhile grown to its final number of 86, which are also being added to the Tautomerizer. The phase of initiating and then making a decision in the IUPAC Working Group about the final set of transforms to be recommended for InChI V2 has been started. Exploratory coding for adding some of the 86 rukes to the current InChI code (v.1.05) were successful for 6 rules. Work on a second-level analysis of tautomerism based on quantum-mechanical calculations and subsequent Deep Learning approaches has been started. Also, X-ray crystallography on a subset of the small molecules mentioned above has been performed. Several manuscripts about this project have been published or are under preparation.