Subramanian G, Paterlini M G, Larson D L, Portoghese P S, Ferguson D M
Department of Medicinal Chemistry and Minnesota Supercomputer Institute, University of Minnesota, Minneapolis, Minnesota 55455, USA.
J Med Chem. 1998 Nov 19;41(24):4777-89. doi: 10.1021/jm9803166.
The three-dimensional structure, dynamics, and binding modes of representative kappa-opioid agonists of the arylacetamide class (U50, 488; U69,593; U62,066; CI-977; ICI199,441; ICI197,067; BRL52,537; and BRL52,656) have been investigated using molecular modeling techniques. Systematic exploration of the conformational space of the ligand combined with molecular dynamics (MD) simulations in water revealed consistent conformational preferences for all the kappa-agonists in this series. The results were further compared with available X-ray and 1D- and 2D-NMR data to identify potential "lead" conformers for molecular docking. Ligand binding modes were initially determined using automated docking of two of the ligands (U50,488 and BRL52,537) to the kappa-opioid receptor. Extrapolation of the predicted binding mode to other members in this ligand series revealed similar docking preferences, with each ligand docked along the receptor helical axis. The binding modes were further refined using MD simulations of the receptor-ligand complexes. The results show a that salt bridge is formed between the amino proton of the ligands and the carboxylate group of Asp138 in TM3. This interaction most likely serves as a key anchoring point for the agonist association. Additional ligand contacts were noted with kappa-specific residues Ile294, Leu295, and Ala298, which may, in part, explain the kappa-selectivity in this series. In comparing the arylacetamides with opiate-based ligands, no evidence was found to link these classes through a common binding motif (except for the ion pair). The binding site model was also applied to explain the enantiomeric preference of U50,488 and to provide insight to the mu/kappa-selectivity of representative ligands in this series. Overall, the results provide a structure-based rationale for ligand recognition that is consistent both with site-directed mutagenesis experiments and structure-function relationship data.
已使用分子建模技术研究了芳基乙酰胺类代表性κ-阿片样物质激动剂（U50,488；U69,593；U62,066；CI-977；ICI199,441；ICI197,067；BRL52,537；和BRL52,656）的三维结构、动力学和结合模式。通过对配体构象空间的系统探索并结合在水中的分子动力学（MD）模拟，揭示了该系列中所有κ-激动剂一致的构象偏好。将结果与现有的X射线以及一维和二维核磁共振数据进一步比较，以确定用于分子对接的潜在“先导”构象。最初通过将两种配体（U50,488和BRL52,537）自动对接至κ-阿片样物质受体来确定配体结合模式。将预测的结合模式外推至该配体系列中的其他成员，显示出相似的对接偏好，每个配体均沿受体螺旋轴对接。使用受体-配体复合物的MD模拟进一步优化结合模式。结果表明，配体的氨基质子与TM3中Asp138的羧基形成了盐桥。这种相互作用很可能是激动剂结合的关键锚定点。还注意到配体与κ特异性残基Ile294、Leu295和Ala298有额外的接触，这可能部分解释了该系列中的κ选择性。在将芳基乙酰胺与基于阿片类的配体进行比较时，未发现证据表明这些类别通过共同的结合基序相连（离子对除外）。结合位点模型还用于解释U50,488的对映体偏好，并为该系列中代表性配体的μ/κ选择性提供见解。总体而言，结果为配体识别提供了基于结构的理论依据，这与定点诱变实验和结构-功能关系数据均一致。
