Rational design and biological evaluation of cell-permeant small molecule agonists and antagonists of the NAADP receptor

细胞可以被认为是微型工厂，蛋白质机器(酶)执行工作，化学信使指示机器启动、停止、更快、更慢。蛋白质机器是根据DNA中写下的指令建造的。所以，既然我们已经知道了整个人类基因组，我们就知道了所有机器的结构，但我们对这些机器是如何共同运作的了解要少得多。研究这个问题的一个非常有效的方法是使用模仿天然化学信使的小分子化学工具。化学信使是在细胞内产生的，通常不会泄漏；小分子化学工具可以很容易地进出细胞，因此它们可以应用于细胞、组织，或者在药物的情况下，作为片剂吞咽。人们希望有化学工具来调节酶的活性，使其抑制(拮抗剂)或刺激(激动剂)。NAADP是一种我们知之甚少的化学信使。我们之前使用计算机筛选了数百万种化学物质，以寻找可能影响对NAADP反应的蛋白质的化学物质。我们发现了一种化合物，Ned-14，可以拮抗NAADP的作用。我们现在想要修改Ned-14的化学结构：(1)获得更好的拮抗剂；(2)寻找激动剂；(3)寻找对胰腺、心脏或神经元具有选择性的拮抗剂和激动剂。这些化学工具将使我们和我们的同事能够更多地了解NAADP在生物学中所扮演的角色。例如，Ned-14已经揭示了NAADP在将葡萄糖感应与胰岛素释放联系起来的分子步骤中的作用。这不仅揭示了新的生物学，而且最终可能导致新的药物靶标和基于药物的疗法的理想化。

Cells can be thought of as minature factories, with protein machines (enzymes) performing the work and chemical messengers instructing the machines to start, stop, faster slower. The protein machines are built from instructions written in DNA. So, now that the entire humane genome is known, we know the structure of all the machines, but we understand far less about how the machines operate together. A very powerful way to investigate this problem is to use small molecule chemical tools that mimic the natural chemical messengers. Chemical messengers are produced within a cell and generally do not leak out; small molecule chemical tools can pass in and out of cells easily, so they can be applied to cells, tissues or, in the case of drugs, swallowed as tablets. It is desireable to have chemical tools that modulate the activity of the enzymes such that they inhibit (antagonists) or stimulate (agonists). NAADP is a chemical messenger for which we know little. We previously used computers to screen millions of chemicals to find ones that might affect the proteins responsive to NAADP. We found a compound, Ned-14, that antagonizes NAADP's action. We now want to modify the chemcial structure of Ned-14: (1) to obtain a better antagonist; (2) to find an agonist; and (3) to find antagonists and agonists that are selective for, say, pancreas, heart or neurons. These chemical tools will enable us and our colleagues to learn more about the roles played by NAADP in biology. For example, Ned-14 already has revealed a role for NAADP in the molecular steps linking glucose sensing to insulin release. Not only does this reveal new biology, but might, ultimately, lead to the ideantification of new drug targets and drug-based therapies.