Distributed Drug Discovery: Advancing Chemical Education through Contextualized Combinatorial Solid-Phase Organic Laboratories
Distributed Drug Discovery: Advancing Chemical Education through Contextualized Combinatorial Solid-Phase Organic Laboratories
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DOI：
10.1021/ed500135n
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发表时间：
2015-05-01
影响因子：
3
通讯作者：
O'Donnell, Martin J.
中科院分区：
文献类型：
--
作者：
Scott, William L.;Denton, Ryan E.;O'Donnell, Martin J.
分布式药物发现（D3）计划培养学生在三个药物发现学科（合成，计算分析和生物筛选），同时解决发现被忽视的疾病的药物线索的重要挑战。本文介绍了在本科有机实验第二学期教学中实施综合实验的方法。该教育计划于2003年在IUPUI开始，已经进行了23个学期，有65个实验室部分，超过1200名学生。由于化学成分是最先进的，它可以作为开发中的计算和生物模块的模型。合成程序是基于有据可查的，可重复的固相组合化学。它们在2 × 3组合网格（Bill-Board）中进行，以产生对照分子和五种新产物（50 μ mol规模，类似于10-20 mg产物，通常高LC/MS纯度）。这些合成方法中的第一种（D3实验室1）利用甘氨酸的受保护和活化的衍生物，其在五步合成序列（烷基化、水解、中和、酰化和从树脂裂解）中转化为含有两个可变多样性元件的N-酰化非天然氨基酸：新的α-侧。链和N-酰基。基于这些组合程序，可以创建和计算分析学生可访问分子的大型虚拟库/目录。然后，选定的分子由D3学生合成和筛选。积极的课堂学习经验和录音讲座或演示被用来教授综合的基本知识和技能，同时使学生能够追求，没有预定的结果，多学科，分布式，以研究为基础的实验，以发现药物。
The Distributed Drug Discovery (D3) program trains students in three drug discovery disciplines (synthesis, computational analysis, and biological screening) while addressing the important challenge of discovering drug leads for neglected diseases. This article focuses on implementation of the synthesis component in the second-semester undergraduate organic laboratory. The educational program Was started at IUPUI in 2003 and has been carried out over 23 semesters with 65 lab sections by >1200 students. Since the chemistry component is most advanced, it serves as a model for the computational and biological modules in development. Synthetic procedures are based on well-documented, reproducible solid-phase combinatorial chemistry. They are carried out in a 2 x 3 combinatorial grid (Bill-Board) to create a control molecule and five new products (50 mu mol scale, similar to 10-20 mg product, typically high LC/MS purity). The first of these synthetic procedures (D3 Lab 1) utilizes a protected and activated derivative of glycine that is converted in a five-step synthetic sequence (alkylation, hydrolysis, neutralization, acylation, and cleavage from the resin) to N-acylated unnatural amino acids containing two variable diversity elements: a new alpha-side. chain and an N-acyl group. Based on these combinatorial procedures, large virtual libraries/catalogs of student-accessible molecules can be created and computationally analyzed. Selected molecules are then synthesized and screened by D3 students. Active classroom learning experiences and recorded lectures or demonstrations are used to teach fundamental knowledge and skills in synthesis while enabling students to pursue, with no predetermined outcome, multidisciplinary, distributed, research-based experiments toward drug-lead discovery.