Gillner M, Bergman J, Cambillau C, Fernström B, Gustafsson J A
Mol Pharmacol. 1985 Oct;28(4):357-63.
In order to identify some of the structural requirements for binding of indoles to the receptor for 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), we have investigated the capacity of various indoles to inhibit specific [1,6-3H]TCDD binding in rat liver cytosol, as analyzed by electrofocusing in polyacrylamide gel. Of these indoles, indolo[3,2-b]carbazole was the most active. The IC50 value for receptor binding of indolo[3,2-b]carbazole as well as for 2,3,7,8-tetrachlorodibenzofuran was 3.6 nM, whereas that of 5,6-benzoflavone was 26 nM. Both indolo[3,2-b]carbazole and 2,3,7,8-tetrachlorodibenzofuran competitively inhibited the binding of [3H]TCDD to the receptor. The well-known microsomal enzyme inducer 3,3'-diindolymethane did not interact significantly with the TCDD receptor. Previous concepts of structure-activity relationships for binding of chlorinated dioxins to the TCDD receptor fail to account for the receptor binding of unhalogenated aryl hydrocarbon hydroxylase inducers such as 5,6-benzoflavone. We have instead considered the true three-dimensional space occupied by some receptor ligands by means of a computer using crystallographic data as inputs. When the atomic van der Waals radii were included, all potent receptor ligands studied could be fitted into a rectangle of 6.8 X 13.7 A.
为了确定吲哚与2,3,7,8-四氯二苯并对二恶英（TCDD）受体结合的一些结构要求，我们研究了各种吲哚抑制大鼠肝细胞溶胶中特异性[1,6-³H]TCDD结合的能力，通过在聚丙烯酰胺凝胶中进行电聚焦分析。在这些吲哚中，吲哚并[3,2-b]咔唑活性最高。吲哚并[3,2-b]咔唑以及2,3,7,8-四氯二苯并呋喃与受体结合的IC50值为3.6 nM，而5,6-苯并黄酮的IC50值为26 nM。吲哚并[3,2-b]咔唑和2,3,7,8-四氯二苯并呋喃均竞争性抑制[³H]TCDD与受体的结合。著名的微粒体酶诱导剂3,3'-二吲哚甲烷与TCDD受体无明显相互作用。先前关于氯化二恶英与TCDD受体结合的构效关系概念无法解释未卤代芳烃羟化酶诱导剂如5,6-苯并黄酮与受体的结合。相反，我们通过计算机利用晶体学数据作为输入来考虑一些受体配体所占据的真实三维空间。当纳入原子范德华半径时，所有研究的强效受体配体都可以拟合到一个6.8×13.7 Å的矩形中。
