Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Clinical and Fundamental Research Center, Renji Hospital , Shanghai Jiao-Tong University School of Medicine , Shanghai 200025 , China.
Medicinal Bioinformatics Center , Shanghai Jiao-Tong University School of Medicine , Shanghai 200025 , China.
J Med Chem. 2019 Jul 25;62(14):6405-6421. doi: 10.1021/acs.jmedchem.8b01749. Epub 2019 Mar 7.
Allosteric modulators bound to structurally diverse allosteric sites can achieve better pharmacological advantages than orthosteric ligands. The discovery of allosteric modulators, however, has been traditionally serendipitous, owing to the complex nature of allosteric modulation. Recent advances in the understanding of allosteric regulatory mechanisms and remarkable availability of structural data of allosteric proteins and modulators, as well as their complexes, have greatly contributed to the development of various computational approaches to guide the structure-based discovery of allosteric modulators. This Perspective first outlines the evolution of the allosteric concept and describes the advantages and hurdles facing allosteric modulator discovery. The current available computational approaches, together with experimental approaches aiming to highlight allosteric studies, are then highlighted, emphasizing successful examples with their combined applications. We aimed to increase the awareness of the feasibility of the structure-based discovery of allosteric modulators using an integrated computational and experimental paradigm.
变构调节剂与结构多样的变构位点结合，可以比正位配体获得更好的药理优势。然而，由于变构调节的复杂性，变构调节剂的发现传统上是偶然的。近年来，人们对变构调节机制的理解有了很大进展，变构蛋白和调节剂及其复合物的结构数据也得到了显著的丰富，这极大地促进了各种基于结构的变构调节剂发现的计算方法的发展。本观点首先概述了变构概念的演变，并描述了变构调节剂发现所面临的优势和障碍。然后突出了当前可用的计算方法，以及旨在强调变构研究的实验方法，强调了它们的联合应用的成功例子。我们的目的是通过综合计算和实验范例，提高人们对基于结构的变构调节剂发现的可行性的认识。
