研究方向：靶向G蛋白偶联受体（GPCR）的药物发现

精神类疾病（如精神分裂症、抑郁症）与多巴胺受体、血清素受体、M型乙酰胆碱受体等单胺类GPCR的功能异常相关。我们以单胺类GPCR为靶标，以“受体-配体”复合物结构为指导，设计合成新型小分子化合物，并进行相应的药理药效研究。研究过程中聚焦解决GPCR药物设计的受体亚型选择性、信号通路偏向性和多靶标药物的合理设计等问题，研究目标是获得具有更优药效、更少毒副作用的新型抗精神疾病候选药物。

• 基于致幻剂机制的5-HT2A受体激动剂设计（Cell 2026；Science 2022；Chem Rev 2024）

• 基于柔性可变骨架的多靶标多功能GPCR药物设计（Cell 2024）

• 多巴胺D2受体部分激动剂设计与新型抗精神分裂症药物发现（Nat Neurosci 2022；J Med Chem 2023）

• 具有抗精神分裂症活性的新型GPR139激动剂发现（J Med Chem 2023）

• 基于PCPMA优势骨架的药物设计（J Med Chem 2020；J Med Chem 2021）

• 腺苷A2a受体拮抗/HDAC活性抑制的双功能抗肿瘤化合物（J Med Chem 2021；J Med Chem 2023；J Med Chem 2026）

1. Wen YT^#,*, Tang LJ^#, Duan WW^#, Ren QF^#, Ni YY^#, Chen SY^#, Chen J^#, Yang L, Wang H, Chen Y, Zheng YZ, Pan XC, Du H, Huang MW, Zeng A, Zhou Z, Zhang ZG, Ji HB, Ge GX, Zeng Y A*, Zhang W*, Wang SH*, Cheng JJ*, Wang S*, Chen JF*. Targeting peripheral 5-HT2AR enhances antitumor immunity in colorectal cancer. Cell 2026, 189, 1-18.

2. Yan W^#,*, Feng M^#, Yang K, Yu C, Zhang W, Liu J, Xie C*, Cheng J*. Pharmacokinetics-Driven Optimization of Immunotherapeutic Agents Targeting the Adenosine A2A Receptor (A2AR) and Histone Deacetylases (HDACs). J Med Chem 2026, 69, 6038−6062.

3. Li R^#, Yan H^#, Chen Y, Liu Y, Tang L, Yu J, Liu J, Wang H, Wang S*, Cheng J*. Structure-Guided Design of Novel 5‑HT_2A Partial Agonists as Psychedelic Analogues with Antidepressant Effects. J Med Chem 2025, 68, 21683−21700.

4. Chen Z#, Yu J#, Wang H#, Xu P#, Fan L, Sun F, Huang S, Zhang P, Huang H, Gu S, Zhang B, Zhou Y, Wan X, Pei G, Xu H.E*, Cheng J*, Wang S*. Flexible scaffold-based cheminformatics approach for polypharmacological drug design. Cell 2024, 187, 2194-2208.

5. Duan W, Cao D, Wang S*, Cheng J*. Serotonin 2A Receptor (5-HT_2AR) Agonists: Psychedelics and Non-Hallucinogenic Analogues as Emerging Antidepressants. Chem Rev 2024, 124, 124-163.

6. Mao J^#, Cui Y^#, Wang H, Duan W, Liu Z-J, Hua T, Zhou N*, Cheng J*.  Design and Synthesis of Novel GPR139 Agonists with Therapeutic Effects in Mouse Models of Social Interaction and Cognitive Impairment. J Med Chem 2023, 66, 14011–14028.

7. Zhang J^#, Feng D^#, Cheng J*, Wuthrich K*. Adenosine A_2A Receptor (A_2AAR) Ligand Screening Using the ¹⁹F-NMR Probe FPPA. J Am Chem Soc 2023, 145, 15061−15064.

8. Liu R^#, Qi J^#, Wang H, Fan L, Zhang P, Yu J, Tan L, Wang S*, Cheng J*. Transformation of a Dopamine D₂ Receptor Agonist to Partial Agonists as Novel Antipsychotic Agents. J Med Chem 2023, 66, 6274−6287.

9. Sun N^#, Yang K^#, Yan W^#, Yao M, Yu C, Duan W, Gu X, Guo D, Jiang H, Xie C*, Cheng J*. Design and Synthesis of Triazole-Containing HDAC Inhibitors That Induce Antitumor Effects and Immune Response. J Med Chem 2023, 66, 4802−4826.

10. Gu X, Yuan H, Zhao W, Sun N, Yan W, Jiang C, He Y, Liu H, Cheng J*, Guo D*. Optical-Controlled Kinetic Switch: Fine-Tuning of the Residence Time of an Antagonist Binding to the Vasopressin V₂ Receptor in In Vitro, Ex Vivo, and In Vivo Models of ADPKD.J Med Chem 2023, 66, 1454−1466.

11. Wang J^#, Wu M^#, Chen Z^#, Wu L, Wang T, Cao D, Wang H, Liu S, Xu Y, Li F, Liu J, Chen N, Zhao S, Cheng J*, Wang S*, Hua T*. The unconventional activation of the muscarinic acetylcholine receptor M4R by diverse ligands. Nat Comm 2022, 13, 2855.

12. Zhang H^#, Yan W^#, Sun Y^#, Yuan H, Su L, Cao X, Wang P, Xu Z, Hu Y, Wang Z, Wang Y, Fu K, Sun Y, Chen Y*, Cheng J*, Guo, D*. Long Residence Time at the Vasopressin V₂ Receptor Translates into Superior Inhibitory Effects in ex vivo and in vivo Models of Autosomal Dominant Polycystic Kidney Disease. J Med Chem, 2022, 65, 7717−7728.

13. Cao D^#, Yu J^#, Wang H^#, Luo Z^#, Liu X^#, He L, Qi J, Fan L, Tang L, Chen Z, Li J, Cheng J*, Wang S*. Structure-based discovery of non-hallucinogenic psychedelic analogs. Science 2022, 375, 403-411.

14. Chen Z^#, Fan L^#, Wang H^#, Yu J^#, Lu D^#, Qi J, Nie F, Luo Z, Liu Z, Cheng J*, Wang S*. Structure-based design of a novel third-generation antipsychotic drug lead with potential antidepressant properties. Nat Neurosci 2022, 25, 39–49.

15. Yan W^#, Fan L^#, Yu J, Liu R, Wang H, Tan L, Wang S*, Cheng J*. 2-Phenylcyclopropyl-methylamine (PCPMA) derivatives as dopamine D₂ receptor partial agonists: Design, synthesis and biological evaluation.J Med Chem 2021, 64, 17239-17258.

16. Yan W^#, Ling L^#, Wu Y, Yang K, Liu R, Zhang J, Zhao S, Zhong G, Zhao S, Jiang H*, Xie C*, Cheng J*. Structure-based design of dual-acting compounds targeting adenosine A_2A receptor and histone deacetylase as novel tumor immunotherapeutic agents. J Med Chem 2021, 64, 16573-16597.

17. Fan L^#, Tan L^#, Chen Z, Qi J, Nie F, Luo Z,Cheng J*, Wang S*. Haloperidol bound D2 dopamine receptor structure inspired the discovery of subtype selective ligands. Nat Commun 2020, 11, 1074.

18. Chan HCS^#, Xu Y^#, Tan L^#, Vogel H, Cheng J*, Wu D*, Yuan S*. Enhancing the Signaling of GPCRs via Orthosteric Ions, ACS Cent Sci 2020, 6, 274−282.

19. Tan L#, Zhou Q#, Yan W, Sun J, Kozikowski AP, Zhao S, Huang X-P*, Cheng J*. Design and Synthesis of Bitopic 2-Phenylcyclopropylmethylamine (PCPMA) Derivatives as Selective Dopamine D3 Receptor Ligands. J Med Chem 2020, 63, 4579-4602.