Molecular shape and medicinal chemistry: a perspective.
Molecular shape and medicinal chemistry: a perspective.
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DOI：
10.1021/jm900818s
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发表时间：
2010-05-27
影响因子：
7.3
通讯作者：
Kelley B
中科院分区：
文献类型：
--
作者：
Nicholls A;McGaughey GB;Sheridan RP;Good AC;Warren G;Mathieu M;Muchmore SW;Brown SP;Grant JA;Haigh JA;Nevins N;Jain AN;Kelley B
马可·奥勒留皇帝在他的哲学沉思《沉思录》中问道：“这个东西，它本身、它自己的构成是什么？它的实质和材料是什么？它的因果本质是什么？” 1 化学，特别是药物化学的历史，是对应用于分子的三个问题的详细阐述：“分子的本质是什么？它是由什么组成的？它会做什么？”在试图回答这些问题并从而描述分子的过程中，我们创造了语言。伟大的作家和化学家普里莫·莱维 (Primo Levi) 在 1984 年抱怨说，描述分子的公认方法只有三种，而且没有一种是很好的：模棱两可的分子式、非词汇化学图和（通常是晦涩难懂的）化学名称。 2 然而，由于这些是我们描述分子“构成”的方式，因此它们主导了我们预测分子功能的方法。即使是大卫·维宁格 (David Weininger) 在李维的哀歌之后不久开发的 SMILES, 3，旨在成为真正的词典描述，也只是促进了依赖于成分元素计数的方法，例如化学经验法则、分类算法、类药物过滤器（例如，无处不在的 54 规则）、2D QSAR 或分子指纹。虽然我们可能已经在元素之外详细阐述了与图形相关的属性（例如，芳香性、疏水性、亲水性、氢键供体和受体等），但这些很少是基本的，而且通常只是对分子行为的看法。为了提高我们的预测能力，我们必须考虑分子的其他“基本”方面，特别是其三维形式。如何最好地捕捉这种“本质”是一个持续研究的主题，本视角详细介绍了分子形状的贡献。形状并不是唯一的方法；例如，众所周知的 3D 药效团概念已被证明非常成功。 5 然而，药效团将原子或原子组描述为空间中的点，分子的含义远不止于此；它们是体积和表面。如本文所述，关注形状的方法在实用性和通用性方面都超越了药效团方法。虽然有些人尝试使用药效团来描述形状，但 6 这样的努力并不是很成功；形状只是一种不同的描述范式。那么我们所说的形状到底是什么意思呢？这个概念有一个简单、普遍的含义，即体积的重合（图 1），也可以扩展到表面。尽管有这个精确且非常笼统的定义，但还有许多不太笼统且更有限的解释。尽管对这些不同的方法都有很好的评论，但我们避免考虑这些方法，以便提出更具凝聚力的观点。 7 然而，我们确实对近似形状的尝试进行了分析。这些方法不可避免地是“有损的”；即，他们为了计算的简单性和速度而交换信息。任何回答奥勒留第一个问题的尝试总是不完整的。正如库恩指出的那样，对科学的理解总是有新的水平。 8 然而，找到一个好的、有用的本质是一项艰巨的工作，因此我们考虑这些近似方法是否值得失去真实性。最初，药物发现中形状的动机是虚拟筛选；如果两个分子具有相似的形状，也许它们具有相似的性质。尽管奎因有句格言“利用相似性概念是科学不成熟的标志”，但 9 形状相似性现在已经是一种相当成熟的方法。然而，衡量一个想法的最真实标准不仅在于其最初构想的有用性，还在于其范围如何随着时间的推移而扩展......
In his philosophic musings “Meditations” the Emperor Marcus Aurelius asks “This thing, what is it in itself, in its own constitution? What is its substance and material? And what its causal nature?” 1 The history of chemistry, and in particular medicinal chemistry, is an elaboration of these three questions as applied to molecules:“What is the essence of a molecule? What is it made of? What will it do?” In trying to answer these questions, and thereby describe molecules, we create languages. Primo Levi, the great writer and chemist, complained in 1984 that there were only three accepted ways to describe a molecule and none of them were very good: the ambiguous molecular formula, the nonlexical chemical graph, and the (often obscure) chemical name. 2 Yet, because these are the ways we describe a molecule’s “constitution”, these dominate our approaches to predicting what a molecule will do. Even SMILES, 3 developed by David Weininger shortly after Levi’s lament, and intended to be a real lexicographic description, only facilitated methods that rely on the counting of elements of composition, eg, chemical rules of thumb, classification algorithms, druglike filters (eg, the ubiquitous rule of five4), 2D QSAR, or molecular fingerprints. While we may have elaborated beyond the elemental to include graph-related properties (eg, aromaticity, hydrophobicity, hydrophilicity, hydrogen bond donors and acceptors, and so forth), these are seldom fundamental and often just opinions on how molecules behave. To further our ability to predict, we have to consider other “essential” aspects of a molecule, in particular its threedimensional form. It is a subject of continuing investigation as to how best to capture this “essence”, and this Perspective details the contribution of molecular shape. Shape is not the only approach; for instance, the well-known concept of 3D pharmacophores has proved very successful. 5 Yet pharmacophores describe atoms or sets of atoms as points in space, and molecules are more than that; they are volumes and surfaces. Approaches that focus on shape, as described here, go beyond pharmacophoric methods in both utility and generality. And while some have tried to use pharmacophores to describe shape, 6 such efforts have not been very successful; shape is simply a different descriptive paradigm. So what do we really mean by shape? There is a simple, universal meaning to the concept as the coincidence of volumes (Figure 1) that can also be extended to surfaces. Despite this precise and very general definition, there are many less general and more limited interpretations. We have avoided considering these approaches in order to present a more cohesive perspective, although there are excellent reviews on these various methods. 7 We do, however, include an analysis of attempts to approximate shape. Such methods are inevitably “lossy”; ie, they trade information for the expediency of computational simplicity and speed. Any attempt to answer the first of Aurelius’ questions is always going to be incomplete; as Kuhn points out, there are always new levels of understanding in science. 8 Yet finding a good and useful essence is hard work, and so we consider if these approximate methods are worth the loss of verisimilitude. Initially the motivation for shape in drug discovery was virtual screening; if two molecules have a similar shape, perhaps they have similar properties. Despite Quine’s adage that “exploiting the similarity concept is a sign of immature science”, 9 shape similarity is now quite a mature approach. Yet the truest measure of an idea is not only its usefulness as originally conceived but also how its ambit expands over time …
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DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
DOI：
10.1107/s0907444904016427
发表时间：
2004-12-01
影响因子：
2.2
作者：
Blanc, E;Roversi, P;Bricogne, G
通讯作者：
Bricogne, G
影响因子：
2.9
作者：
Fry, David C.
通讯作者：
Fry, David C.
影响因子：
2.9
作者：
Ballester, Pedro J.;Finn, Paul W.;Richards, W. Graham
通讯作者：
Richards, W. Graham
影响因子：
7.3
作者：
Barrow, James C.;Stauffer, Shaun R.;Vacca, Joseph P.
通讯作者：
Vacca, Joseph P.