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Discovery and characterization of steroid derivatives as hCES2A inhibitors
Yueyang Cao1, Jiayi Luo1, Yong Yang2
1State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000, People's Republic of China.
Abstract:
Human carboxylesterase 2A (hCES2A) is a key mediator of drug metabolism and chemotherapeutic side effects, necessitating potent and selective inhibitors. Herein, 42 novel steroid derivatives were rationally designed via hCES2A homology modeling and synthesized. Compound 3g emerged as the lead inhibitor, exhibiting strong hCES2A inhibitory activity (IC₅₀ = 1.257 μM) and excellent selectivity, with no cross-inhibition on hCES1A, hAchE, or hBchE. Structure-activity relationship (SAR) analysis and a validated 3D-QSAR model identified steric and hydrophobic effects as key activity determinants. Mechanistic studies confirmed 3g acts as a competitive inhibitor (Ki = 1.503 μM) with favorable binding affinity (Kd = 1.00 μM). Molecular docking revealed 3g occupies the hCES2A catalytic triad (Ser-228, Glu-345, His-457) pocket, stabilized by π-π stacking with Phe-106/Phe-469. Critical cellular validation was performed via high-content imaging, which confirmed specific hCES2A inhibition in HepG2 cells. Additionally, 3g exhibits low cytotoxicity and good metabolic stability. In conclusion, compound 3g was identified as a potent inhibitor of hCES2A.
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