In Silico Design and Selection of New Tetrahydroisoquinoline-Based CD44 Antagonist Candidates
| Autor: | Atilio Reyes-Romero, Angel J Ruiz-Moreno, Marco A. Velasco-Velázquez, Alexander Dömling |
|---|---|
| Přispěvatelé: | Drug Design, Medicinal Chemistry and Bioanalysis (MCB) |
| Rok vydání: | 2021 |
| Předmět: |
Stereochemistry
In silico Pharmaceutical Science Plasma protein binding Molecular Dynamics Simulation Article Analytical Chemistry lcsh:QD241-441 03 medical and health sciences chemistry.chemical_compound Mice 0302 clinical medicine lcsh:Organic chemistry Tetrahydroisoquinolines/chemistry Neoplasms Tetrahydroisoquinolines Drug Discovery Molecule Animals Humans Physical and Theoretical Chemistry Binding site Hyaluronic Acid CD44 030304 developmental biology Hyaluronan Receptors/antagonists & inhibitors 0303 health sciences Binding Sites pharmacophore Tetrahydroisoquinoline Drug discovery Organic Chemistry computational combinatorial chemistry molecular dynamics Neoplasms/drug therapy Hyaluronan Receptors chemistry Chemistry (miscellaneous) Docking (molecular) 030220 oncology & carcinogenesis Drug Design Molecular Medicine Pharmacophore tetrahydroisoquinoline Hyaluronic Acid/metabolism Protein Binding |
| Zdroj: | Molecules Molecules, 26(7):1877. MDPI AG Molecules, Vol 26, Iss 1877, p 1877 (2021) Volume 26 Issue 7 |
| ISSN: | 1420-3049 1431-5157 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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