Department of Oncology, Cross Cancer Institute, University of Alberta, 11560 University Avenue, Edmonton, AB T6G 1Z2, Canada.
Chem Biol Drug Des. 2013 Mar;81(3):359-81. doi: 10.1111/cbdd.12082. Epub 2012 Dec 26.
Soluble guanylate cyclase is a heterodimer receptor that functions in several signal transduction pathways. Conversion of guanosine 5'-triphosphate to 3',5'-cyclic monophosphate second messenger at the catalytic domain is regulated by the changes at heme nitric oxide/oxygen domain of the β-subunit. To better understand conformational changes at heme site that may impact on activities of catalytic domain, three soluble guanylate cyclase homolog proteins with heme at Fe-His state were investigated, and their dynamic behaviors were monitored in both unliganded (apo) and complex with heme. As a result of dynamic conformational changes, Lys110, Asp45, Arg135, and Glu41 were found interacting with the site gate, which may interfere with transportation of small molecules in and out of the heme site. An alternative binding site adjacent to that of heme was identified. Binding affinity of several nitric oxide-independent activators and heme-dependent stimulators was examined, and their binding modes in the heme site and in the alternative binding site in the human soluble guanylate cyclase enzyme were computationally simulated. The calculated binding energies were used as criteria to filter results of virtual high-throughput screenings based on FlexX ligand-docking algorithm and absorption, distribution, metabolism, excretion, and toxicity properties on databases of available drugs. The identified drugs from virtual high-throughput screening have been suggested for experimental investigations, based on which they may either be directly repurposed or require structural modifications for better physico-chemical and pharmacological properties.
可溶性鸟苷酸环化酶是一种异二聚体受体，在几种信号转导途径中发挥作用。催化结构域中鸟苷 5'-三磷酸转化为 3'，5'-环单磷酸第二信使受β亚基血红素一氧化氮/氧结构域变化的调节。为了更好地了解血红素部位可能影响催化结构域活性的构象变化，研究了三种具有血红素处于 Fe-His 状态的可溶性鸟苷酸环化酶同源蛋白，并监测了它们在无配体（apo）和与血红素复合物中的动态行为。由于动态构象变化，发现 Lys110、Asp45、Arg135 和 Glu41 与位点门相互作用，这可能干扰小分子在血红素部位内外的运输。鉴定了一个与血红素相邻的替代结合位点。检查了几种一氧化氮非依赖性激活剂和血红素依赖性刺激剂的结合亲和力，并在人可溶性鸟苷酸环化酶酶的血红素部位和替代结合部位进行了计算模拟。计算出的结合能被用作基于 FlexX 配体对接算法的虚拟高通量筛选结果的筛选标准，以及基于现有药物数据库的吸收、分布、代谢、排泄和毒性特性。从虚拟高通量筛选中鉴定出的药物已被建议进行实验研究，根据这些研究，它们可以直接重新利用，也可以需要进行结构修饰以获得更好的物理化学和药理学特性。
