Background: In this study, the anti-colorectal cancer (CRC) activities of 40 glycyrrhetinic acid derivatives were proposed and evaluated by the molecular docking method, which allowed the flexibility of both ligand-receptor, with twelve CRC-related targets.
Methods: The proposed derivatives, which clearly distinguish isomers at position 18 as well as the different tautomers, were divided into five groups, including (1) glycyrrhetinic acid and its oxidation derivatives, (2) glycoside derivatives, (3) 3β-amine derivatives, (4) five-membered heterocyclic ring-combined derivatives, and (5) six-membered heterocyclic ring-combined derivatives.
Results: Finally, four out of twelve proposed targets related to CRC with good binding affinities to the proposed glycyrrhetinic acid derivatives were selected, including Epidermal Growth Factor Receptor (EGFR), Focal Adhesion Kinase (FAK), Lactate Dehydrogenase A (LDHA), and Thymidylate Synthase (TS).
Conclusion: From there, 9/40 derivatives for EGFR (pKd ≥ 9); 10/40 derivatives for FAK (pKd ≥ 10); 9/40 derivatives for LDHA (pKd ≥ 10), and 6/40 derivatives for TS (pKd ≥ 9) were also obtained. The glycoside derivatives showed the best binding affinity (especially the glucuronide derivative 5b), followed by the 3β-amino derivatives (especially the 3β-(phenylamino) derivative 8b) and the five-membered heterocyclic ring-combined derivatives (especially the pyrrole derivative 10a or pyrazole derivative 11.2a), while the six-membered heterocyclic ring-combined derivatives had less potential to inhibit the 4 selected targets.
Keywords: Molecular docking, colorectal cancer, glycyrrhetinic acid, heterocyclic ring, Surflex-Dock, pyrazole derivative.