Development and Testing of New Computational Methods for Ligand Discovery and Mechanism

摘要 我们的长期目标是开发基于结构和化学信息学的方法，用于配体的发现、测试 这些都在实验模型系统中，并将它们应用于具有生物学意义的目标。给读者一个 根据我们的方向感，我们在四个大焦点内勾勒出几个问题： A.开发新的对接方法并在简化的洞穴等模型系统中进行测试，其中 单独的条款可能会被解开。几个即将到来的项目利用了我们的超大型库 在上一期中介绍的，包括：I.更大的库总是更好的吗，或者在一定的库大小的情况下 饱和？二、随着图书馆的发展，我们是仍然受到类生物分子的束缚，还是偏离了 这些?这对对接命中质量有何影响？三、我们能把数百亿到数万亿的图书馆 有更好的方法和前瞻性的模式匹配的分子？我们也在探索IV。柔性受体 对接在模型空腔中，以及V.配体构象和解溶菌株的处理。 B.颠覆以结构为基础的企业，我们回到经典药理学的逻辑 现代化学信息学，寻求从他们的配体预测目标。利用过去一段时间的工作，我们 调查广泛使用的分子，如中性药物，是否有特定的靶点和II。使用网络 寻找分子来调节被SARS-CoV-2病毒蛋白颠覆的人类靶点。 C.将这些方法应用于生物感兴趣的目标，通常是GPCRs。在即将到来的时期，我们将。 探索为智能GPCR量身定做的超大型图书馆；将适用范围扩大到运输机； 三、寻找酵母交配因子GPCRSte2的化学探针，以补充酵母遗传学的力量。 胶体聚集和磷脂沉积在早期药物发现中的作用。即将到来的项目 期间调查一。利用胶体聚集体进行药物输送；二。探讨其致病机制。 胶体聚集及其在早期发现中的影响；调查一种新现象，它可能 对基于细胞的配体发现的广泛影响，磷脂沉积症。 这个Mira之前是由五个赠款资助的，它的广度反映了这一点。虽然雄心勃勃，但它的实用主义 上一阶段的生产率和广泛的初步结果支持了这一点。

Abstract Our long-term goal is to develop structure-based and chemoinformatic methods in ligand discovery, testing these in experimental model systems and applying them to targets of biological interest. To give the reader a sense of our direction, we sketch several questions within four broad foci: A. Development of new docking methods and their testing in model systems like simplified cavity sites, where individual terms may be disentangled. Several upcoming projects leverage the ultra-large libraries we introduced in the last period, including: i. are bigger libraries always better, or at some library size do we saturate? ii. As the library grows, are we still bounded by bio-like molecules, or do we diverge away from these? How does this affect docking hit quality? iii. Can we treat libraries of tens-of-billions to trillions of molecules with better methods and look-ahead pattern matching? We are also exploring iv. flexible receptor docking in the model cavities, and v. treatment of ligand conformational and desolvation strain. B. Turning the structure-based enterprise on its head, we return to the logic of classical pharmacology with modern chemoinformatics, seeking to predict targets from their ligands. Leveraging work in the last period, we i. Investigate if widely consumed molecules, such as neutraceuticals, have specific targets and ii. Use network pharmacology to find molecules to modulate the human targets subverted by SARS-Cov-2 viral proteins. C. Application of these methods to biologically interesting targets, often GPCRs. In the upcoming period, we i. explore bespoke ultra-large libraries for amingergic GPCRs; ii. Extend domain of applicability to transporters; iii. Seek chemical probes for the yeast mating-factor GPCR Ste2 to complement the power of yeast genetics. D. The role of colloidal aggregation and phospholipidosis in early drug discovery. Projects in the upcoming period investigate i. Exploiting colloidal aggregates for drug delivery; ii. Investigating the mechanism of colloidal aggregation and its impact in early discovery; iii. Investigating a new phenomenon that may have wide impact on cell-based ligand discovery, phospholipidosis. This MIRA was previously funded by five grants, and its breadth reflects that. While ambitious, its pragmatism is supported by the productivity of the last period and by extensive preliminary results.