Vistoli Giulio, Pedretti Alessandro, Mazzolari Angelica, Testa Bernard
Dipartimento di Scienze Farmaceutiche Università degli Studi di Milano, Milan, Italy.
University of Lausanne, Lausanne, Switzerland.
Methods Mol Biol. 2018;1800:245-274. doi: 10.1007/978-1-4939-7899-1_12.
With a view to introducing the concept of pharmacological space and its potential applications in investigating and predicting the toxic mechanisms of xenobiotics, this opening chapter describes the logical relations between conformational behavior, physicochemical properties and binding spaces, which are seen as the three key elements composing the pharmacological space. While the concept of conformational space is routinely used to encode molecular flexibility, the concepts of property spaces and, particularly, of binding spaces are more innovative. Indeed, their descriptors can find fruitful applications (a) in describing the dynamic adaptability a given ligand experiences when inserted into a specific environment, and (b) in parameterizing the flexibility a ligand retains when bound to a biological target. Overall, these descriptors can conveniently account for the often disregarded entropic factors and as such they prove successful when inserted in ligand- or structure-based predictive models. Notably, and although binding space parameters can clearly be derived from MD simulations, the chapter will illustrate how docking calculations, despite their static nature, are able to evaluate ligand's flexibility by analyzing several poses for each ligand. Such an approach, which represents the founding core of the binding space concept, can find various applications in which the related descriptors show an impressive enhancing effect on the statistical performances of the resulting predictive models.
为了引入药理空间的概念及其在研究和预测外源性物质毒性机制方面的潜在应用，本章开篇描述了构象行为、物理化学性质和结合空间之间的逻辑关系，这三者被视为构成药理空间的三个关键要素。虽然构象空间的概念通常用于编码分子柔性，但性质空间尤其是结合空间的概念更具创新性。实际上，它们的描述符可以在以下方面找到富有成效的应用：(a) 描述给定配体插入特定环境时所经历的动态适应性，以及 (b) 参数化配体与生物靶点结合时保留的柔性。总体而言，这些描述符可以方便地解释常常被忽视的熵因素，因此当插入基于配体或基于结构的预测模型时，它们证明是成功的。值得注意的是，尽管结合空间参数显然可以从分子动力学模拟中得出，但本章将说明对接计算尽管具有静态性质，却能够通过分析每个配体的多个构象来评估配体的柔性。这种方法代表了结合空间概念的核心基础，可在各种应用中找到，其中相关描述符对所得预测模型的统计性能显示出令人印象深刻的增强效果。
