Biotechnology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; School of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran.
School of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran.
Bioorg Chem. 2021 Dec;117:105411. doi: 10.1016/j.bioorg.2021.105411. Epub 2021 Oct 8.
During the past decades, histamine H receptors have received widespread attention in pharmaceutical research due to their involvement in pathophysiology of several diseases such as neurodegenerative disorders. In this context, blocking of these receptors is of paramount importance in progression of such diseases. In the current investigation, novel histamine H receptor ligands were designed by exploiting scaffold-hopping drug-design strategy. We inspected the designed molecules in terms of ADME properties, drug-likeness, as well as toxicity profiles. Additionally molecular docking and dynamics simulation studies were performed to predict binding mode and binding free energy calculations, respectively. Among the designed structures, we selected compound d2 and its demethylated derivative as examples for synthesis and affinity measurement. In vitro binding assays of the synthesized molecules demonstrated that d2 has lower binding affinity (K = 2.61 μM) in radioligand displacement assay to hHR than that of demethylated form (K = 12.53 μM). The newly designed compounds avoid of any toxicity predictors resulted from extended in silico and experimental studies, can offer another scaffold for histamine HR antagonists for further structure-activity relationship studies.
在过去的几十年中，由于组胺 H 受体参与了多种疾病（如神经退行性疾病）的病理生理学，因此它们在药物研究中受到了广泛关注。在这种情况下，阻断这些受体对于这些疾病的进展至关重要。在当前的研究中，我们利用药物设计的“骨架跳跃”策略设计了新型的组胺 H 受体配体。我们从 ADME 特性、类药性以及毒性特征等方面检查了设计的分子。此外，还进行了分子对接和动力学模拟研究，分别预测了结合模式和结合自由能计算。在所设计的结构中，我们选择了化合物 d2 及其去甲基衍生物作为合成和亲和力测量的示例。合成分子的体外结合实验表明，与去甲基形式（K=12.53 μM）相比，d2 在放射性配体置换测定中对 hHR 的结合亲和力较低（K=2.61 μM）。新设计的化合物避免了任何毒性预测指标，这是通过扩展的计算和实验研究得出的，它们可以为组胺 HR 拮抗剂提供另一个支架，用于进一步的构效关系研究。
