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

2009年出版的《逃离平原》（Escape from flatland）显示了临床试验中潜在先导化合物的成功与sp3杂化碳的存在之间的相关性，这表明更多的3D分子有更好的机会成为药物，可能是由于它们更高的溶解度和更好地与3D蛋白质腔体相匹配。然而，从那时起，它已被证明，扁平核心支架是同样好的起点，为访问3D形状空间的3D核心支架。这表明，通过选择替代物和官能团，可以实现药物发现成功率提高所需的3D形状，同时仍然保持芳香，扁平的支架核心。这是一个理想的前景，因为引入sp3杂化碳所需的化学过程更具挑战性且更耗时。此外，小的芳族杂环的化学仍然在很大程度上未被探索，如通过创建VENULE-虚拟探索性杂环库所示。VERAYLE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，这些系统中只有1701个（约7%）被合成并在文献中报告。然而，作者的分析表明，数据库中超过3000个额外的分子被预测为可合成的。这显示了新的化学空间探索和引入新的化学结构的潜力，在设计具有独特分子结构的化学探针和药物时，同时使用已知的和更简单的杂环化学。该项目的目的是开发一种计算工具，Heterocycle Isostere Explorer（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的主要功能将是使用形状、静电势和矢量相似性来搜索VENULE数据库中的杂环生物电子等排体。这种建议电子等排体的方法将HCIE与其他电子等排体搜索工具（如SwissBioisostere）区分开来，因为它不需要任何先前的生物电子等排体替代知识来进行预测，因此将导致新的电子等排体建议。此外，还将对VERELLE数据库进行分析，以寻找目前勘探不足的“平地”地区，这些地区可能存在新的物理化学性质空间。最后，将开发用于分析VERELLE中杂环化合物的合成易处理性和预测合成路线的软件，并将其纳入HCIE，帮助用户将新的杂环化合物纳入其目标分子和从头设计软件。这些预测将通过尝试合成一些以前没有合成的杂环在VERELLE验证。该项目福尔斯以下EPSRC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Paul Brennan和Fernanda Duarte教授监督，并与Exscientia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.