Zarzycka Barbara, Seijkens Tom, Nabuurs Sander B, Ritschel Tina, Grommes Jochen, Soehnlein Oliver, Schrijver Roy, van Tiel Claudia M, Hackeng Tilman M, Weber Christian, Giehler Fabian, Kieser Arnd, Lutgens Esther, Vriend Gert, Nicolaes Gerry A F
Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University , 6200 MD Maastricht, The Netherlands.
J Chem Inf Model. 2015 Feb 23;55(2):294-307. doi: 10.1021/ci500631e. Epub 2015 Jan 27.
The CD154-CD40 receptor complex plays a pivotal role in several inflammatory pathways. Attempts to inhibit the formation of this complex have resulted in systemic side effects. Downstream inhibition of the CD40 signaling pathway therefore seems a better way to ameliorate inflammatory disease. To relay a signal, the CD40 receptor recruits adapter proteins called tumor necrosis factor receptor-associated factors (TRAFs). CD40-TRAF6 interactions are known to play an essential role in several inflammatory diseases. We used in silico, in vitro, and in vivo experiments to identify and characterize compounds that block CD40-TRAF6 interactions. We present in detail our drug docking and optimization pipeline and show how we used it to find lead compounds that reduce inflammation in models of peritonitis and sepsis. These compounds appear to be good leads for drug development, given the observed absence of side effects and their demonstrated efficacy for peritonitis and sepsis in mouse models.
CD154-CD40受体复合物在多种炎症信号通路中起关键作用。抑制该复合物形成的尝试已导致全身性副作用。因此，对CD40信号通路进行下游抑制似乎是改善炎症性疾病的更好方法。为了传递信号，CD40受体招募称为肿瘤坏死因子受体相关因子（TRAFs）的衔接蛋白。已知CD40与TRAF6的相互作用在多种炎症性疾病中起重要作用。我们通过计算机模拟、体外和体内实验来鉴定和表征阻断CD40与TRAF6相互作用的化合物。我们详细介绍了我们的药物对接和优化流程，并展示了我们如何利用它来寻找在腹膜炎和脓毒症模型中减轻炎症的先导化合物。鉴于观察到这些化合物没有副作用且在小鼠模型中对腹膜炎和脓毒症具有已证实的疗效，它们似乎是药物开发的良好先导物。
