Wei Jing, Li Hui, Qu Wanlu, Gao Qingzhi
Tianjin University, PR China.
Neurochem Int. 2009 Dec;55(7):637-42. doi: 10.1016/j.neuint.2009.06.006. Epub 2009 Jun 18.
Adenosine is known to act as a neuromodulator by suppressing synaptic transmission in the central and peripheral nervous system. A(3) adenosine receptor (A(3)AR) antagonists were recently considered as potential drugs for the treatment of cardiac ischemia and inflammation diseases. To better understand the chemical features responsible for the recognition mechanism and the receptor-ligand interaction, we have performed the molecular simulation study combined with a virtual library screening process to develop novel A(3)AR antagonists. A series of A(3)AR selective antagonists, including triazolopurines, imidazopurines, pyrrolopurines, and quinazolines were employed to dock into the A(3)AR binding site via AUTODOCK software. The putative binding mode for each compound was proposed. Three main hydrophobic pockets, one hydrogen bonding with Asn250, and one pi-pi interaction with Phe168 for all antagonists were identified. The most favorable binding conformations served as the templates for pharmacophore modeling with Catalyst 4.11 and a virtually generated library have been screened for novel antagonist development.
已知腺苷通过抑制中枢和外周神经系统中的突触传递来充当神经调节剂。A(3)腺苷受体（A(3)AR）拮抗剂最近被认为是治疗心脏缺血和炎症性疾病的潜在药物。为了更好地理解负责识别机制和受体-配体相互作用的化学特征，我们进行了分子模拟研究，并结合虚拟库筛选过程来开发新型A(3)AR拮抗剂。一系列A(3)AR选择性拮抗剂，包括三唑并嘌呤、咪唑并嘌呤、吡咯并嘌呤和喹唑啉，通过AUTODOCK软件对接至A(3)AR结合位点。提出了每种化合物的假定结合模式。确定了所有拮抗剂的三个主要疏水口袋、一个与Asn250的氢键以及一个与Phe168的π-π相互作用。最有利的结合构象用作使用Catalyst 4.11进行药效团建模的模板，并筛选了一个虚拟生成的库以开发新型拮抗剂。
