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Extrahelical Binding Site for a 1H-Imidazo[4,5-c]quinolin-4-amine A3Adenosine Receptor Positive Allosteric Modulator on Helix 8 and Distal Portions of Transmembrane Domains 1 and 7
Molecular Pharmacology ( IF 3.2 ) Pub Date : 2024-03-01 , DOI: 10.1124/molpharm.123.000784
Courtney L. Fisher , Matteo Pavan , Veronica Salmaso , Robert F. Keyes , Tina C. Wan , Balaram Pradhan , Zhan-Guo Gao , Brian C. Smith , Kenneth A. Jacobson , John A. Auchampach

This study describes the localization and computational prediction of a binding site for the A3 adenosine receptor (A3AR) positive allosteric modulator 2-cyclohexyl-1H-imidazo[4,5-c]quinolin-4-(3,4-dichlorophenyl)amine (LUF6000). The work reveals an extrahelical lipid-facing binding pocket disparate from the orthosteric binding site that encompasses transmembrane domain (TMD) 1, TMD7, and Helix (H) 8, which was predicted by molecular modeling and validated by mutagenesis. According to the model, the nearly planar 1H-imidazo[4,5-c]quinolinamine ring system lies parallel to the transmembrane segments, inserted into an aromatic cage formed by π-π stacking interactions with the side chains of Y2847.55 in TMD7 and Y2938.54 in H8 and by π-NH bonding between Y2847.55 and the exocyclic amine. The 2-cyclohexyl group is positioned “upward” within a small hydrophobic subpocket created by residues in TMDs 1 and 7, while the 3,4-dichlorophenyl group extends toward the lipid interface. An H-bond between the N-1 amine of the heterocycle and the carbonyl of G291.49 further stabilizes the interaction. Molecular dynamics simulations predicted two metastable intermediates, one resembling a pose determined by molecular docking and a second involving transient interactions with Y2938.54; in simulations, each of these intermediates converges into the final bound state. Structure-activity-relationships for replacement of either of the identified exocyclic or endocyclic amines with heteroatoms lacking H-bond donating ability were consistent with the hypothetical pose. Thus, we characterized an allosteric pocket for 1H-imidazo[4,5-c]quinolin-4-amines that is consistent with data generated by orthogonal methods, which will aid in the rational design of improved A3AR positive allosteric modulators.

中文翻译:

螺旋 8 以及跨膜域 1 和 7 远端部分上 1H-咪唑并[4,5-c]喹啉-4-胺 A3 腺苷受体正变构调节剂的螺旋外结合位点

本研究描述了 A 3腺苷受体 (A 3 AR) 正变构调节剂 2-环己基-1 H -咪唑并[4,5-c]喹啉-4-(3,4-) 结合位点的定位和计算预测二氯苯基)胺(LUF6000)。这项工作揭示了一个与正位结合位点不同的螺旋外脂质结合袋,该结合位点包含跨膜结构域 (TMD) 1、TMD7 和螺旋 (H) 8,这是通过分子模型预测并通过诱变验证的。根据该模型,近平面的1 H-咪唑并[4,5-c]喹啉胺环系统与跨膜片段平行,插入与TMD7中Y284 7.55的侧链通过π-π堆积相互作用形成的芳香笼中H8中的Y293 8.54和Y284 7.55与环外胺之间的π-NH键合。 2-环己基位于“向上”,位于 TMD 1 和 7 中的残基形成的小疏水亚袋内,而 3,4-二氯苯基则向脂质界面延伸。杂环的N - 1胺和G29 1.49的羰基之间的H-键进一步稳定了相互作用。分子动力学模拟预测了两种亚稳态中间体,一种类似于分子对接确定的姿势,另一种涉及与 Y293 8.54的瞬时相互作用;在模拟中,这些中间体中的每一个都会收敛到最终的束缚态。用缺乏氢键供给能力的杂原子取代已识别的环外或环内胺的结构-活性关系与假设的姿势一致。因此,我们表征了 1 H -咪唑并[4,5-c]喹啉-4-胺的变构口袋,该变构口袋与正交方法生成的数据一致,这将有助于合理设计改进的 A 3 AR 正变构调节剂。
更新日期:2024-02-15
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