Wang Mukuo, Hou Shujing, Wei Yu, Li Dongmei, Lin Jianping
State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, China.
Biodesign Center, Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, Tianjin, China.
PLoS Comput Biol. 2021 Mar 19;17(3):e1008821. doi: 10.1371/journal.pcbi.1008821. eCollection 2021 Mar.
Adenosine receptors (ARs) have been demonstrated to be potential therapeutic targets against Parkinson's disease (PD). In the present study, we describe a multistage virtual screening approach that identifies dual adenosine A1 and A2A receptor antagonists using deep learning, pharmacophore models, and molecular docking methods. Nineteen hits from the ChemDiv library containing 1,178,506 compounds were selected and further tested by in vitro assays (cAMP functional assay and radioligand binding assay); of these hits, two compounds (C8 and C9) with 1,2,4-triazole scaffolds possessing the most potent binding affinity and antagonistic activity for A1/A2A ARs at the nanomolar level (pKi of 7.16-7.49 and pIC50 of 6.31-6.78) were identified. Further molecular dynamics (MD) simulations suggested similarly strong binding interactions of the complexes between the A1/A2A ARs and two compounds (C8 and C9). Notably, the 1,2,4-triazole derivatives (compounds C8 and C9) were identified as the most potent dual A1/A2A AR antagonists in our study and could serve as a basis for further development. The effective multistage screening approach developed in this study can be utilized to identify potent ligands for other drug targets.
腺苷受体（ARs）已被证明是对抗帕金森病（PD）的潜在治疗靶点。在本研究中，我们描述了一种多阶段虚拟筛选方法，该方法使用深度学习、药效团模型和分子对接方法来识别腺苷A1和A2A受体双重拮抗剂。从包含1,178,506种化合物的ChemDiv库中筛选出19个命中化合物，并通过体外试验（cAMP功能试验和放射性配体结合试验）进行进一步测试；在这些命中化合物中，鉴定出两种具有1,2,4-三唑骨架的化合物（C8和C9），它们对A1/A2A ARs具有最强的结合亲和力和拮抗活性，在纳摩尔水平（pKi为7.16 - 7.49，pIC50为6.31 - 6.78）。进一步的分子动力学（MD）模拟表明，A1/A2A ARs与两种化合物（C8和C9）之间的复合物具有类似的强结合相互作用。值得注意的是，在我们的研究中，1,2,4-三唑衍生物（化合物C8和C9）被鉴定为最有效的A1/A2A AR双重拮抗剂，可作为进一步开发的基础。本研究中开发的有效的多阶段筛选方法可用于识别其他药物靶点的有效配体。
