Brazilian Biosciences National Laboratory (LNBio), National Centre for Research in Energy and Materials (CNPEM), 13083-970 Campinas, SP, Brazil.
Nat Prod Rep. 2020 Apr 1;37(4):488-514. doi: 10.1039/c9np00064j. Epub 2020 Feb 12.
Covering: 2008 to 2018Over the last decade more than two hundred single natural products were confirmed as natural allosteric modulators (alloNPs) of proteins. The compounds are presented and discussed with the support of a chemical space, constructed using a principal component analysis (PCA) of molecular descriptors from chemical compounds of distinct databases. This analysis showed that alloNPs are dispersed throughout the majority of the chemical space defined by natural products in general. Moreover, a cluster of alloNPs was shown to occupy a region almost devoid of allosteric modulators retrieved from a dataset composed mainly of synthetic compounds, further highlighting the importance to explore the entire natural chemical space for probing allosteric mechanisms. The protein targets which alloNPs bind to comprised 81 different proteins, which were classified into 5 major groups, with enzymes, in particular hydrolases, being the main representative group. The review also brings a critical interpretation on the mechanisms by which alloNPs display their molecular action on proteins. In the latter analysis, alloNPs were classified according to their final effect on the target protein, resulting in 3 major categories: (i) local alteration of the orthosteric site; (ii) global alteration in protein dynamics that change function; and (iii) oligomer stabilisation or protein complex destabilisation via protein-protein interaction in sites distant from the orthosteric site. G-protein coupled receptors (GPCRs), which use a combination of the three types of allosteric regulation found, were also probed by natural products. In summary, the natural allosteric modulators reviewed herein emphasise their importance for exploring alternative chemotherapeutic strategies, potentially pushing the boundaries of the druggable space of pharmacologically relevant drug targets.
2008 年至 2018 年
在过去的十年中，已有两百多种单一天然产物被确认为蛋白质的天然别构调节剂（alloNPs）。本综述通过使用来自不同数据库的化合物分子描述符的主成分分析（PCA）构建化学空间，支持对这些化合物进行介绍和讨论。该分析表明，alloNPs 分散在一般天然产物定义的化学空间的大部分区域。此外，还显示出 alloNPs 簇占据了一个几乎没有来自主要由合成化合物组成的数据集检索到的别构调节剂的区域，这进一步强调了探索整个天然化学空间以探测别构机制的重要性。alloNPs 结合的蛋白质靶标包括 81 种不同的蛋白质，这些蛋白质被分为 5 个主要组，其中酶，特别是水解酶，是主要的代表性组。该综述还对 alloNPs 对蛋白质显示其分子作用的机制进行了批判性解释。在后者的分析中，根据 alloNPs 对靶蛋白的最终影响对其进行分类，导致 3 个主要类别：（i）变构部位的局部改变；（ii）改变功能的蛋白质动力学的全局改变；和（iii）通过与变构部位远离的部位的蛋白质-蛋白质相互作用稳定寡聚体或蛋白质复合物。天然产物也探测了 G 蛋白偶联受体（GPCR），其使用三种类型的变构调节的组合。总之，本文综述的天然别构调节剂强调了它们在探索替代化学治疗策略方面的重要性，可能会推动药理学相关药物靶标可药用空间的边界。
