Kaczor Agnieszka A, Targowska-Duda Katarzyna M, Budzyńska Barbara, Biała Grażyna, Silva Andrea G, Castro Marián
Department of Synthesis and Chemical Technology of Pharmaceutical Substances, Faculty of Pharmacy with Division of Medical Analytics, Medical University of Lublin, 4A Chodzki St., PL-20093 Lublin, Poland; School of Pharmacy, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland.
Department of Biopharmacy, Faculty of Pharmacy with Division of Medical Analytics, Medical University of Lublin, 4A Chodzki St., PL-20093 Lublin, Poland.
Neurochem Int. 2016 Jun;96:84-99. doi: 10.1016/j.neuint.2016.03.003. Epub 2016 Mar 8.
Antipsychotics currently available to treat schizophrenia suffer several limitations: (1) they are efficient against positive but not negative and cognitive symptoms of the disease; (2) they help only a half of patients; (3) they have severe side effects including neurological and metabolic side effects. Thus, novel drugs to treat schizophrenia are highly demanded. We identified a novel dopamine D2 receptor antagonist, D2AAK1, with Ki of 58 nM using structure-based virtual screening. D2AAK1 possesses additional nanomolar or low micromolar affinity to D1, D3, 5-HT1A and 5-HT2A receptors, making it an ideal candidate for a multi-target drug. Here we present homology modeling, molecular docking and molecular dynamics of D2AAK1 and its molecular targets and animal studies of D2AAK1 as a potential antipsychotic. The main contact of D2AAK1 and all the receptors studied is the electrostatic interaction between the protonable nitrogen atom of the ligand and the conserved Asp(3.32) as typical for orthosteric ligands of aminergic GPCRs. We confirmed antagonistic/partial agonistic properties of D2AAK1 towards all the receptors in in vitro essays and in in silico studies as the ligand stabilizes the ionic lock interaction. We also demonstrated neuroleptic, anxiolytic and, importantly, procognitive properties of D2AAK1 in mouse models.
（1）它们对该疾病的阳性症状有效，但对阴性和认知症状无效；（2）它们仅对一半的患者有帮助；（3）它们有严重的副作用，包括神经和代谢副作用。因此，迫切需要治疗精神分裂症的新型药物。我们通过基于结构的虚拟筛选鉴定出一种新型多巴胺D2受体拮抗剂D2AAK1，其解离常数（Ki）为58 nM。D2AAK1对D1、D3、5-HT1A和5-HT2A受体具有额外的纳摩尔或低微摩尔亲和力，使其成为多靶点药物的理想候选者。在此，我们展示了D2AAK1及其分子靶点的同源建模、分子对接和分子动力学，以及D2AAK1作为潜在抗精神病药物的动物研究。D2AAK1与所有研究的受体的主要接触是配体的可质子化氮原子与保守的天冬氨酸（Asp(3.32)）之间的静电相互作用，这是胺能G蛋白偶联受体（GPCR）的正构配体的典型特征。我们在体外实验和计算机模拟研究中证实了D2AAK1对所有受体的拮抗/部分激动特性，因为该配体稳定了离子锁定相互作用。我们还在小鼠模型中证明了D2AAK1的抗精神病、抗焦虑以及重要的促认知特性。
