Institute of General and Ecological Chemistry, Faculty of Chemistry, Lodz University of Technology, Żeromskiego 116, 90-924 Lodz, Poland.
Remedika, Sustekova, 1 85104 Bratislava, Slovakia.
Molecules. 2020 Mar 3;25(5):1135. doi: 10.3390/molecules25051135.
The success of innovative drugs depends on an interdisciplinary and holistic approach to their design and development. The supramolecular architecture of living systems is controlled by non-covalent interactions to a very large extent. The latter are prone to extensive cooperation and like a virtuoso play a symphony of life Thus, the design of effective ligands should be based on thorough knowledge on the interactions at either a molecular or high topological level. In this work, we emphasize the importance of supramolecular structure and ligand-based design keeping the potential of supramolecular H-bonding synthons in focus. In this respect, the relevance of supramolecular chemistry for advanced therapies is appreciated and undisputable. It has developed tools, such as Hirshfeld surface analysis, using a huge data on supramolecular interactions in over one million structures which are deposited in the Cambridge Structure Database (CSD). In particular, molecular interaction surfaces are useful for identification of macromolecular active sites followed by docking experiments. Ornithine-derived compounds are a new, promising class of multi-targeting ligands for innovative therapeutics and cosmeceuticals. In this work, we present the synthesis together with the molecular and supramolecular structure of a novel ornithine derivative, namely -α,-δ)-dibenzoyl-(α)-hydroxymethylornithine, . It was investigated by modern experimental and methods in detail. The incorporation of an aromatic system into the ornithine core induces stacking interactions, which are vital in biological processes. In particular, rare C=Oπ intercontacts have been identified in . Supramolecular interactions were analyzed in all structures of ornithine derivatives deposited in the CSD. The influence of substituent was assessed by the Hirshfeld surface analysis. It revealed that the crystal packing is stabilized mainly by HO, OH, CH, Cl (Br, F)H and OO interactions. Additionally, ππ, C-Hπ and N-Oπ interactions were also observed. All relevant H-bond energies were calculated using the Lippincott and Schroeder H-bond model. A library of synthons is provided. In addition, the large synthons () were considered. The DFT optimization either or yields very similar molecular species. The major difference with the relevant crystal structure was related to the conformation of terminal benzoyl C15-C20 ring. Furthermore, prediction of the extensive physicochemical ADME profile (absorption, distribution, metabolism and excretion) related to the drug-likeness and medicinal chemistry friendliness revealed that a novel ornithine derivative has the potential to be a new drug candidate. It has shown good absorption and very low toxicity.
创新药物的成功取决于其设计和开发的跨学科和整体方法。生命系统的超分子结构在很大程度上受到非共价相互作用的控制。后者容易广泛合作，就像一位演奏家演奏交响乐一样，演绎着生命的乐章。因此，有效的配体设计应该基于对分子或高拓扑水平相互作用的透彻了解。在这项工作中，我们强调了超分子结构和基于配体的设计的重要性，同时关注超分子氢键合成子的潜力。在这方面，超分子化学对于先进疗法的相关性和无可争议的重要性得到了认可。它开发了工具，例如使用超过 100 万个结构中超过 100 万个超分子相互作用数据的 Hirshfeld 表面分析。特别是，分子相互作用表面可用于识别大分子活性部位，然后进行对接实验。鸟氨酸衍生化合物是一类用于创新治疗和化妆品的新型多靶标配体。在这项工作中，我们介绍了一种新型鸟氨酸衍生物，即-α，-δ）-二苯甲酰-（α）-羟甲基鸟氨酸的合成及其分子和超分子结构。通过现代实验和计算方法对其进行了详细研究。在鸟氨酸核心中引入芳基系统会诱导堆积相互作用，这在生物过程中至关重要。特别是，在 中已经鉴定出罕见的 C=Oπ相互作用。对 CSD 中所有鸟氨酸衍生物结构的超分子相互作用进行了分析。通过 Hirshfeld 表面分析评估取代基的影响。结果表明，晶体堆积主要由 HO、OH、CH、Cl（Br、F）H 和 OO 相互作用稳定。此外，还观察到了ππ、C-Hπ和 N-Oπ相互作用。使用 Lippincott 和 Schroeder H-bond 模型计算了所有相关 H-bond 能量。提供了一个合成子库。此外，还考虑了大合成子（）。DFT 优化 或 得到非常相似的分子物种。与相关晶体结构的主要区别与末端苯甲酰 C15-C20 环的构象有关。此外，与药物相似性和药物化学友好性相关的广泛物理化学 ADME 概况（吸收、分布、代谢和排泄）的预测表明，新型鸟氨酸衍生物 有可能成为新的候选药物。它表现出良好的吸收和非常低的毒性。
