Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, Maryland 21201, USA.
J Phys Chem B. 2013 Jul 3;117(26):7907-17. doi: 10.1021/jp404238n. Epub 2013 Jun 24.
Molecular details of μ opioid receptor activations were obtained using molecular dynamics simulations of the receptor in the presence of three agonists, three antagonists, and a partial agonist and on the constitutively active T279K mutant. Agonists have a higher probability of direct interactions of their basic nitrogen (N) with Asp147 as compared with antagonists, indicating that direct ligand-Asp147 interactions modulate activation. Medium-size substituents on the basic N of antagonists lead to steric interactions that perturb N-Asp147 interactions, while additional favorable interactions occur with larger basic N substituents, such as in N-phenethylnormorphine, restoring N-Asp147 interactions, leading to agonism. With the orvinols, the increased size of the C19 substituent in buprenorphine over diprenorphine leads to increased interactions with residues adjacent to Asp147, partially overcoming the presence of the cyclopropyl N substituent, such that buprenorphine is a partial agonist. Results also indicate different conformational properties of the intracellular regions of the transmembrane helices in agonists versus antagonists.
使用存在三种激动剂、三种拮抗剂和一种部分激动剂以及组成型激活的 T279K 突变体的μ阿片受体的分子动力学模拟，获得了μ阿片受体激活的分子细节。与拮抗剂相比，激动剂的碱性氮 (N) 更有可能与天冬氨酸 147 发生直接相互作用，这表明直接配体-天冬氨酸 147 相互作用调节激活。拮抗剂碱性 N 上的中等大小取代基会导致空间位阻相互作用，从而破坏 N-天冬氨酸 147 相互作用，而较大的碱性 N 取代基会产生额外的有利相互作用，例如在 N-苯乙基-去甲吗啡中，恢复 N-天冬氨酸 147 相互作用，从而导致激动作用。对于奥芬醇类药物，丁丙诺啡中 C19 取代基的增大超过二丙诺啡，导致与天冬氨酸 147 相邻的残基的相互作用增加，部分克服了环丙基 N 取代基的存在，使得丁丙诺啡成为部分激动剂。结果还表明，激动剂与拮抗剂的跨膜螺旋细胞内区域具有不同的构象特性。
