Generating Diverse Pilot-Scale Libraries for Screening

描述（由申请人提供）：过去十年见证了科学知识和技术的显著进步，这些进步将对人类健康产生重大影响。随着人类和其他基因组的测序，新的基因、基因产物、信号传导和代谢途径正以快速的速度被发现，从而导致许多潜在的治疗靶点的鉴定，否则这些靶点将是未知的。确定活性的生物测定已经导致发现了许多具有有希望的生理化学和生理特性的小分子。相反，小分子越来越多地成为探测生物功能和机制的宝贵工具。尽管已经取得了惊人的进展，但仍然存在的一个重大挑战在于鉴定具有新化学型和结构的生物活性小分子。这个问题最好通过化学合成新的官能化杂环框架来解决，这些杂环框架可以很容易地进行阐述以优化生物活性。因此，我们将应用我们为功能化杂环支架的多样性导向合成而独特开发的化学方法，以制备不同的新型化合物的纯样品（>90%），并提交给NIH分子图书馆小分子储存库（MLSMR）。这些小分子将衍生自一系列大约25-30种不同的杂环支架，其中一些在结构上和功能上都很复杂，具有不同的取代模式，这些取代模式被明确设计为最佳地占据生物靶标的三维空间。每个分子集合的设计都是基于合理的生物学原理。例如，所提出的库的许多成员是天然产物，而其他成员则体现了已知的特权结构。在合成每个文库之前，将采用包括多样性作图在内的计算方法，以确保集合中的最大结构多样性。将通过应用各种标准指标（包括Lipinski Rule of Five）来验证集合中的单个成员是否为药物样。每个分子将具有允许进一步发展结构活性关系的功能性。预计提交给MLSMR的化合物将在广泛的测定中表现出生物活性，并作为探索生物功能的有用工具，从而导致疾病治疗的显著改善。

DESCRIPTION (provided by applicant): The past decade has witnessed remarkable advances in scientific knowledge and technology that will have significant impacts upon human health. With the sequencing of the human and other genomes, new genes, gene products, signaling and metabolic pathways are being discovered at a rapid pace, thereby leading to the identification of numerous potential therapeutic targets that would have otherwise been unknown. Biological assays to determine activities have led to the discovery of numerous small molecules that have promising physiochemical and physiological properties. Conversely, small molecules are increasingly serving as invaluable tools to probe biological function and mechanism. Despite the stunning progress that has been made, one significant challenge that remains lies in identifying biologically active small molecules having novel chemotypes and structures. This problem is best addressed by the chemical synthesis of new, functionalized heterocyclic frameworks that may be easily elaborated to optimize biological activity. We will thus apply chemistry we have uniquely developed for the diversity-oriented synthesis of functionalized, heterocyclic scaffolds to prepare pure (>90%) samples of collections of distinct, novel compounds for submission to the NIH Molecular Libraries Small-Molecule Repository (MLSMR). These small molecules will be derived from a series of approximately 25-30 different heterocyclic scaffolds, some of which are both structurally and functionally complex, having different substitution patterns that are explicitly designed to optimally occupy three-dimensional space of the biological target. The design of each collection of molecules is based upon a sound biological rationale. For example, many members of the proposed libraries are natural product-like, whereas others embody known privileged structures. Prior to the synthesis of each library, computational methods, including diversity mapping, will be employed to ensure maximal structural diversity in the collection. Individual members of the collections will be verified as drug-like by application of various standard metrics, including the Lipinski Rule of Five. Each molecule will bear functionality that will allow for further development of structure activity relationships. It is expected that compounds submitted to the MLSMR will exhibit biological activities in a broad range of assays and serve as useful tools to explore biological function, thereby leading to significant improvements in disease treatment.