Dipartimento di Scienze Farmaceutiche Pietro Pratesi, Facoltà di Farmacia, Università degli Studi di Milano, Via Mangiagalli, 25, I-20133 Milano, Italy.
Future Med Chem. 2011 Jun;3(8):995-1010. doi: 10.4155/fmc.11.54.
In the last few years, a need to account for molecular flexibility in drug-design methodologies has emerged, even if the dynamic behavior of molecular properties is seldom made explicit. For a flexible molecule, it is indeed possible to compute different values for a given conformation-dependent property and the ensemble of such values defines a property space that can be used to describe its molecular variability; a most representative case is the lipophilicity space. In this review, a number of applications of lipophilicity space and other property spaces are presented, showing that this concept can be fruitfully exploited: to investigate the constraints exerted by media of different levels of structural organization, to examine processes of molecular recognition and binding at an atomic level, to derive informative descriptors to be included in quantitative structure--activity relationships and to analyze protein simulations extracting the relevant information. Much molecular information is neglected in the descriptors used by medicinal chemists, while the concept of property space can fill this gap by accounting for the often-disregarded dynamic behavior of both small ligands and biomacromolecules. Property space also introduces some innovative concepts such as molecular sensitivity and plasticity, which appear best suited to explore the ability of a molecule to adapt itself to the environment variously modulating its property and conformational profiles. Globally, such concepts can enhance our understanding of biological phenomena providing fruitful descriptors in drug-design and pharmaceutical sciences.
在过去的几年中，即使分子性质的动态行为很少被明确说明，在药物设计方法中考虑分子柔性的需求也已经出现了。对于柔性分子，确实可以为给定构象依赖性性质计算不同的值，并且此类值的集合定义了可以用来描述其分子可变性的性质空间；最具代表性的情况是亲脂性空间。在这篇综述中，提出了亲脂性空间和其他性质空间的许多应用，表明这个概念可以得到很好的利用：研究不同层次结构组织的介质施加的约束，在原子水平上检查分子识别和结合的过程，推导包含在定量结构-活性关系中的信息描述符，并分析提取相关信息的蛋白质模拟。药物化学家在使用的描述符中忽略了很多分子信息，而性质空间的概念可以通过考虑小分子配体和生物大分子经常被忽视的动态行为来填补这一空白。性质空间还引入了一些创新概念，如分子敏感性和可塑性，这些概念似乎最适合探索分子适应环境的能力，从而可以改变其性质和构象特征。总体而言，这些概念可以增强我们对生物现象的理解，为药物设计和药物科学提供富有成效的描述符。
