In Silico Design and Selection of New Tetrahydroisoquinoline-Based CD44 Antagonist Candidates

Angel J Ruiz-Moreno, Atilio Reyes-Romero, Alexander Dömling*, Marco A Velasco-Velázquez*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

3 Citations (Scopus)
86 Downloads (Pure)


CD44 promotes metastasis, chemoresistance, and stemness in different types of cancer and is a target for the development of new anti-cancer therapies. All CD44 isoforms share a common N-terminal domain that binds to hyaluronic acid (HA). Herein, we used a computational approach to design new potential CD44 antagonists and evaluate their target-binding ability. By analyzing 30 crystal structures of the HA-binding domain (CD44HAbd), we characterized a subdomain that binds to 1,2,3,4-tetrahydroisoquinoline (THQ)-containing compounds and is adjacent to residues essential for HA interaction. By computational combinatorial chemistry (CCC), we designed 168,190 molecules and compared their conformers to a pharmacophore containing the key features of the crystallographic THQ binding mode. Approximately 0.01% of the compounds matched the pharmacophore and were analyzed by computational docking and molecular dynamics (MD). We identified two compounds, Can125 and Can159, that bound to human CD44HAbd (hCD44HAbd) in explicit-solvent MD simulations and therefore may elicit CD44 blockage. These compounds can be easily synthesized by multicomponent reactions for activity testing and their binding mode, reported here, could be helpful in the design of more potent CD44 antagonists.

Original languageEnglish
Article number1877
Number of pages17
Issue number7
Publication statusPublished - 2021


  • Animals
  • Binding Sites
  • Drug Design
  • Drug Discovery
  • Humans
  • Hyaluronan Receptors/antagonists & inhibitors
  • Hyaluronic Acid/metabolism
  • Mice
  • Molecular Dynamics Simulation
  • Neoplasms/drug therapy
  • Protein Binding
  • Tetrahydroisoquinolines/chemistry


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