In Silico Design and Selection of New Tetrahydroisoquinoline-Based CD44 Antagonist Candidates
Angel J Ruiz-Moreno1,2,3,4, Atilio Reyes-Romero4, Alexander Dömling4
1Departamento de Farmacología, Facultad de Medicina, Universidad Nacional Autónoma de Mexico (UNAM), Ciudad de Mexico 04510, Mexico.
Abstract:
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.
Insights
Researchers designed novel CD44 antagonists using computational methods. Two compounds, Can125 and Can159, show potential for blocking CD44, a key target in cancer therapy, offering new avenues for drug development.
Area of Science:
- Biochemistry
- Computational Chemistry
- Drug Discovery
Background:
- CD44 is crucial for cancer progression, including metastasis, chemoresistance, and stemness.
- CD44's hyaluronic acid (HA)-binding domain is a validated target for anti-cancer therapies.
Purpose of the Study:
- To computationally design and identify novel antagonists targeting the HA-binding domain of CD44.
- To evaluate the binding potential of designed compounds to human CD44 HA-binding domain (hCD44HAbd).
Main Methods:
- Analysis of 30 crystal structures of CD44 HA-binding domain (CD44HAbd).
- Computational combinatorial chemistry (CCC) to generate 168,190 potential molecules.
- Pharmacophore modeling, computational docking, and molecular dynamics (MD) simulations.
Main Results:
- Identified a subdomain within CD44HAbd that binds 1,2,3,4-tetrahydroisoquinoline (THQ)-containing compounds.
- Designed and screened over 168,000 molecules, with 0.01% matching the pharmacophore.
- Two compounds, Can125 and Can159, demonstrated binding to hCD44HAbd in MD simulations.
Conclusions:
- Can125 and Can159 are promising lead compounds for CD44 antagonist development.
- The identified binding mode provides a basis for designing more potent CD44 inhibitors.
- These compounds are synthetically accessible, facilitating further experimental validation.
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