Chillin' in Flatland - Development of HCIE (Heterocycle Isostere Explorer)

2009年出版的《Escape from Platland》显示了临床试验中潜在先导的成功与SP3杂化碳的存在之间的相关性，这表明更多的3D分子更有可能成为药物，可能是因为它们更高的溶解度，更适合3D蛋白质腔。然而，从那时起，已经证明平芯支架与3D芯支架一样是访问3D形状空间的良好起点。这表明，通过选择取代基和官能团，可以实现在药物发现中获得更大成功所需的3D形状，同时保持芳香的、扁平的支架核心。这是一个可取的前景，因为引入SP3杂化碳所需的化学物质更具挑战性，也更耗时。此外，小分子芳香族杂环化合物的化学仍未得到很大程度的探索，如载体-虚拟探索性杂环文库的创建所表明的那样。Vehicle是一个理论上可能的杂芳环系统的数据库，由大约25000个分子组成。在2008年创建时，只有1701个系统(约7%)被综合起来并在文献中进行了报道。然而，作者的分析表明，数据库中预计有3000多个额外的分子是易于人工处理的。这表明，在利用已知和更简单的杂环化学的同时，在设计具有独特分子结构的化学探针和药物时，有可能进行新的化学空间探索和引入新的化学结构。该项目的目的是开发一种计算工具，杂环等温探测器(HCIE)，以发现新的杂环核心，用于化学探针开发和药物发现中的化合物优化。HCIE的主要功能是利用形状、静电势和载体相似性搜索杂环生物等位基因载体数据库。这种建议等位线的方法使HCIE不同于其他等位线搜索工具，如SwissBioisstere，因为它不需要任何先前关于生物等位线替代的知识来进行预测，从而将导致新的等位线建议。此外，将对车辆数据库进行分析，以搜索目前勘探不足的“平地”区域，并可能提出新的物理化学性质空间。最后，将开发分析车载杂环合成可操作性和预测合成路线的软件，并将其整合到HCIE中，帮助用户将新的杂环引入他们的目标分子和从头设计软件。然后，这些预测将通过尝试在车辆中合成一些以前未合成的杂环来验证。该项目属于EPSRC的以下研究领域：计算和理论化学、化学生物学和生物化学以及合成有机化学。它将由保罗·布伦南教授和费尔南达·杜阿尔特教授监督，并与ExScience a合作进行。

The 2009 publication "Escape from flatland" shows a correlation between a success of potential leads in clinical trials and the presence of sp3 hybridised carbons, suggesting that more 3D molecules have a better chance of becoming drugs, possibly due to their higher solubility and better fit with the 3D protein cavities. However, since then it has been shown that flat core scaffolds are equally good starting points for accessing 3D shape space as 3D core scaffolds. This suggest that the 3D shape desired for increased success in drug discovery could be achieved through a choice of substitutes and functional groups, while still keeping the aromatic, flat scaffold cores. That is a desirable prospect, as the chemistry required to introduce sp3 hybridised carbons is more challenging and time-consuming. Moreover, the chemistry of small, aromatic heterocycles is still largely unexplored as shown by the creation of VEHICLe - virtual exploratory heterocyclic library. VEHICLe is a database of theoretically possible heteroaromatic ring systems, consisting of around 25000 molecules. At the time of its creation, in 2008, only 1701 of those systems (around 7%) have been synthesized and reported in literature. However, the authors' analysis has shown that more than 3000 additional molecules in the database are predicted to be synthetically tractable. This shows a potential for new chemical space exploration and introduction of new chemical structures in design of chemical probes and drugs with unique molecular architectures, while using the already known and simpler chemistry of heterocycles. The aim of this project would be to develop a computational tool, the HeteroCycle Isostere Explorer (HCIE) to discover new heterocyclic cores for compound optimisation in chemical probe development and drug discovery. The main function of HCIE would be to search the VEHICLe database for heterocycle bioisosteres using shape, electrostatic potential and vector similarity. This method of suggesting isosteres distinguishes HCIE from other isostere search tools, like SwissBioisostere, in that it doesn't require any previous knowledge of bioisosteric replacements to make its predictions and thus will to lead to novel isostere suggestions. Additionally, the VEHICLe database would be analysed to search for areas of "flatland" that are currently underexplored and could present novel physicochemical property spaces. Lastly, software to analyse the synthetic tractability and predict synthesis routes for heterocycles in VEHICLe would be developed and incorporated into HCIE, helping the user to incorporate novel heterocycles into their target molecules and de novo design software. Those predictions would then be validated by attempting to synthesize some of the not previously synthesized heterocycles in VEHICLe. This project falls within the following EPSRC research areas: Computational and theoretical chemistry, Chemical biology and biological chemistry and Synthetic organic chemistry. It would be supervised by Professors Paul Brennan and Fernanda Duarte and conducted in collaboration with Exscientia.