2. Academic Validation
  3. Flexible scaffold-based cheminformatics approach for polypharmacological drug design

Flexible scaffold-based cheminformatics approach for polypharmacological drug design

  • Cell. 2024 Apr 25;187(9):2194-2208.e22. doi: 10.1016/j.cell.2024.02.034.
Zhangcheng Chen 1,  Jing Yu 1,  Huan Wang 2,  Peiyu Xu 3,  Luyu Fan 4,  Fengxiu Sun 1,  Sijie Huang 3,  Pei Zhang 1,  He Huang 5,  Shuo Gu 5,  Bowen Zhang 5,  Yue Zhou 1,  Xiaobo Wan 5,  Gang Pei 1,  H Eric Xu 6,  Jianjun Cheng 7,  Sheng Wang 8
Affiliations

Affiliations

  • 1 Key Laboratory of Multi-Cell Systems, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China.
  • 2 iHuman Institute, ShanghaiTech University, Shanghai 201210, China.
  • 3 State Key Laboratory of Drug Research, Center for Structure and Function of Drug Targets, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 4 Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China.
  • 5 ComMedX, Beijing 100094, China.
  • 6 State Key Laboratory of Drug Research, Center for Structure and Function of Drug Targets, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: eric.xu@simm.ac.cn.
  • 7 iHuman Institute, ShanghaiTech University, Shanghai 201210, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China. Electronic address: chengjj@shanghaitech.edu.cn.
  • 8 Key Laboratory of Multi-Cell Systems, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China; Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China. Electronic address: wangsheng@sibcb.ac.cn.
PMID: 38552625 DOI: 10.1016/j.cell.2024.02.034
Abstract

Effective treatments for complex central nervous system (CNS) disorders require drugs with polypharmacology and multifunctionality, yet designing such drugs remains a challenge. Here, we present a flexible scaffold-based cheminformatics approach (FSCA) for the rational design of polypharmacological drugs. FSCA involves fitting a flexible scaffold to different receptors using different binding poses, as exemplified by IHCH-7179, which adopted a "bending-down" binding pose at 5-HT2AR to act as an antagonist and a "stretching-up" binding pose at 5-HT1AR to function as an agonist. IHCH-7179 demonstrated promising results in alleviating cognitive deficits and psychoactive symptoms in mice by blocking 5-HT2AR for psychoactive symptoms and activating 5-HT1AR to alleviate cognitive deficits. By analyzing aminergic receptor structures, we identified two featured motifs, the "agonist filter" and "conformation shaper," which determine ligand binding pose and predict activity at aminergic receptors. With these motifs, FSCA can be applied to the design of polypharmacological ligands at Other receptors.

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