Structure determination of antiviral compound SCH 38057 complexed with human rhinovirus 14.
Structure determination of antiviral compound SCH 38057 complexed with human rhinovirus 14.
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DOI：
10.1006/jmbi.1993.1206
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发表时间：
1993-04
影响因子：
5.6
通讯作者：
A. Zhang;R. Nanni;T. Li;G. F. Arnold;D. Oren;A. Jacobo-Molina;R. Williams;G. Kamer;D. Rubenstein;Y. Li
中科院分区：
文献类型：
--
作者：
A. Zhang;R. Nanni;T. Li;G. F. Arnold;D. Oren;A. Jacobo-Molina;R. Williams;G. Kamer;D. Rubenstein;Y. Li
SCH 38057（1-[6-（2-氯-4-甲氧基苯氧基）-己基]咪唑盐酸盐）是一种新型水溶性抗病毒化合物，对多种小核糖核酸病毒感染具有抑制活性。采用同步辐射X射线单晶衍射技术，以3.0 A分辨率测定了人鼻病毒14（HRV 14）与SCH 38057复合物的结构。发现SCH 38057结合在衣壳蛋白VP 1内疏水口袋的最内端，这是其他抗小核糖核酸病毒药物结合的位点;然而，该复合物在两个重要方面与先前报道的复合物不同。它在装订口袋的入口附近留下了相当大的空间。此外，VP 1多肽构象的改变与在HRV 14与其他抗病毒剂的复合物中观察到的相似，但更广泛。尽管VP 1中只有9个氨基酸与SCH 38057分子密切接触（在3.6 A内），但VP 1和VP 3中至少有36个氨基酸的构象发生了显著改变（相对于天然分子，C α移动> 0.5 A）。比较了HRV 14与SCH 38057和WIN 51711的配合物的结构。小核糖核酸病毒衣壳残基和抗病毒抑制剂之间的芳环相互作用被认为是这些化合物定位的主要决定因素之一。
SCH 38057 (1-[6-(2-chloro-4-methoxyphenoxy)-hexyl]imidazole hydrochloride) is a new, water-soluble antiviral compound that has inhibitory activities against a number of picornavirus infections. The structure of the human rhinovirus 14 (HRV14) complex with SCH 38057 was determined at 3.0 A resolution by single-crystal diffraction techniques using synchrotron X-radiation. SCH 38057 was found to bind at the innermost end of the hydrophobic pocket within the capsid protein VP1, a locus of binding of other antipicornaviral agents; however, the complex differs from previously reported complexes in two important aspects. It leaves a considerable volume near the entrance to the binding pocket unoccupied. In addition, the alterations in the conformation of the VP1 polypeptide are similar to, but more extensive than those observed in HRV14 complexes with other antiviral agents. Although only 9 amino acids of VP1 have close contacts with the SCH 38057 molecule (within 3.6 A), at least 36 amino acids from both VP1 and VP3 have significantly altered conformations (C alpha movement > 0.5 A versus native). The structures of complexes of HRV14 with SCH 38057 and WIN 51711 are compared. Aromatic ring interactions between picornavirus capsid residues and antiviral inhibitors are proposed to be among the major determinants for positioning of these compounds.