Drug Design, Development and Therapy (Jul 2020)

Structural Insight into the Mechanism of 4-Aminoquinolines Selectivity for the alpha2A-Adrenoceptor

  • Li Z,
  • Li J,
  • Liu L,
  • Deng W,
  • Liu Q,
  • Liu R,
  • Zhang W,
  • He Z,
  • Fan L,
  • Yang Y,
  • Duan Y,
  • Hou H,
  • Wang X,
  • Yang Z,
  • Wang X,
  • Chen S,
  • Wang Y,
  • Huang N,
  • Chen J

Journal volume & issue
Vol. Volume 14
pp. 2585 – 2594

Abstract

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Zaibing Li,1,2,* Jingyu Li,1,* Liyan Liu,1 Wenyi Deng,3 Qingrong Liu,4 Ruofan Liu,4 Wen Zhang,3 Zaiqing He,5 Lei Fan,6 Yingzhuo Yang,7 Yun Duan,7 Huifang Hou,1 Xinyuan Wang,1 Zhimei Yang,1 Xiaoying Wang,1 Shanze Chen,1 Yi Wang,1 Ning Huang,1 Junli Chen1 1Department of Pathophysiology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu 610041, People’s Republic of China; 2Department of Pathophysiology, School of Basic Medical Science, Southwest Medical University, Luzhou, Sichuan 646000, People’s Republic of China; 3West China Medical School, Sichuan University, Chengdu 610041, People’s Republic of China; 4West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu 610041, People’s Republic of China; 5Department of Pathology, Nuclear of Industry 416 Hospital, Chengdu, Sichuan 610051, People’s Republic of China; 6Department of Occupational Medicine, Nuclear of Industry 416 Hospital, Chengdu, Sichuan 610051, People’s Republic of China; 7Department of Nuclear Medicine, Sichuan Cancer Hospital, Chengdu 610041, People’s Republic of China*These authors contributed equally to this workCorrespondence: Junli Chen; Ning Huang Email [email protected]; [email protected]: α2A-adrenoceptor (AR) is a potential target for the treatment of degenerative diseases of the central nervous system, and α2A-AR agonists are effective drugs for this condition. However, the lack of high selectivity for α2A-AR subtype of traditional drugs greatly limits their clinic usage.Methods: A series of homobivalent 4-aminoquinolines conjugated by two 4-aminoquinoline moieties via varying alkane linker length (C2-C12) were characterized for their affinities for each α2-AR subtype. Subsequently, docking, molecular dynamics and mutagenesis were applied to uncover the molecular mechanism.Results: Most 4-aminoquinolines (4-aminoquinoline monomer, C2-C6, C8-C10) were selective for α2A-AR over α2B- and α2C-ARs. Besides, the affinities are of similar linker length-dependence for each α2-AR subtype. Among all the compounds tested, C10 has the highest affinity for α2A-AR (pKi=− 7.45± 0.62), which is 12-fold and 60-fold selective over α2B-AR and α2C-AR, respectively. Docking and molecular dynamics suggest that C10 simultaneously interacts with orthosteric and “allosteric” sites of the α2A-AR. The mutation of F205 decreases the affinity by 2-fold. The potential allosteric residues include S90, N93, E94 and W99.Conclusion: The specificity of C10 for the α2A-AR and the potential orthosteric and allosteric binding sites proposed in this study provide valuable guidance for the development of novel α2A-AR subtype selective compounds.Keywords: alpha2-adrenoceptor, selectivity, linker length, allosteric modulation

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