Ridgway Harry, Moore Graham J, Mavromoustakos Thomas, Tsiodras Sotirios, Ligielli Irene, Kelaidonis Konstantinos, Chasapis Christos T, Gadanec Laura Kate, Zulli Anthony, Apostolopoulos Vasso, Petty Russell, Karakasiliotis Ioannis, Gorgoulis Vassilis G, Matsoukas John M
Institute for Sustainable Industries and Liveable Cities, Victoria University, Melbourne, Australia.
AquaMem Consultants, Rodeo, NM, USA.
Comput Struct Biotechnol J. 2022;20:2091-2111. doi: 10.1016/j.csbj.2022.04.010. Epub 2022 Apr 9.
The discovery and facile synthesis of a new class of sartan-like arterial antihypertensive drugs (angiotensin receptor blockers [ARBs]), subsequently referred to as "bisartans" is reported. results and complementary molecular modelling presented in this communication indicate bisartans may be beneficial for the treatment of not only heart disease, diabetes, renal dysfunction, and related illnesses, but possibly COVID-19. Bisartans are novel bis-alkylated imidazole sartan derivatives bearing dual symmetric anionic biphenyl tetrazole moieties. docking and molecular dynamics studies revealed bisartans exhibited higher binding affinities for the ACE2/spike protein complex (PDB 6LZG) compared to all other known sartans. They also underwent stable docking to the Zn domain of the ACE2 catalytic site as well as the critical interfacial region between ACE2 and the SARS-CoV-2 receptor binding domain. Additionally, semi-stable docking of bisartans at the arginine-rich furin-cleavage site of the SARS-CoV-2 spike protein (residues 681-686) required for virus entry into host cells, suggest bisartans may inhibit furin action thereby retarding viral entry into host cells. Bisartan tetrazole groups surpass nitrile, the pharmacophoric "warhead" of PF-07321332, in its ability to disrupt the cysteine charge relay system of 3CLpro. However, despite the apparent targeting of multifunctional sites, bisartans do not inhibit SARS-CoV-2 infection in bioassays as effectively as PF-07321332 (Paxlovid).
本文报道了一类新型的类沙坦动脉降压药物(血管紧张素受体阻滞剂[ARBs])的发现及其简便合成方法,这类药物随后被称为“双沙坦”。本通讯中呈现的结果及补充的分子模型表明,双沙坦不仅可能对治疗心脏病、糖尿病、肾功能不全及相关疾病有益,还可能对治疗新冠肺炎有益。双沙坦是带有双对称阴离子联苯四唑基团的新型双烷基化咪唑沙坦衍生物。对接和分子动力学研究表明,与所有其他已知沙坦相比,双沙坦对ACE2/刺突蛋白复合物(PDB 6LZG)表现出更高的结合亲和力。它们还能稳定地对接至ACE2催化位点的锌结构域以及ACE2与SARS-CoV-2受体结合结构域之间的关键界面区域。此外,双沙坦在病毒进入宿主细胞所需的SARS-CoV-2刺突蛋白富含精氨酸的弗林蛋白酶切割位点(第681 - 686位氨基酸残基)的半稳定对接表明,双沙坦可能抑制弗林蛋白酶的作用,从而延缓病毒进入宿主细胞。双沙坦的四唑基团在破坏3CLpro的半胱氨酸电荷中继系统的能力上超过了PF - 07321332的药效基团“弹头”腈基。然而,尽管双沙坦明显靶向多个功能位点,但在生物测定中,其抑制SARS-CoV-2感染的效果不如PF - 07321332(帕罗韦德)。