Phenylphthalazines as small-molecule inhibitors of urea transporter UT-B and their binding model
| Autor: | Jian-hua Ran, Weng-Ieong Tou, Tianluo Lei, Hong Zhou, Calvin Yu-Chian Chen, Min Li, Baoxue Yang |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Erythrocytes Urea transporter Stereochemistry Small Molecule Libraries Mice Structure-Activity Relationship 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Animals Humans Structure–activity relationship Pharmacology (medical) Binding site IC50 Pharmacology Sulfonamides biology Membrane transport protein Membrane Transport Proteins General Medicine Small molecule Molecular Docking Simulation 030104 developmental biology Urea transport Biochemistry chemistry 030220 oncology & carcinogenesis biology.protein Urea Phthalazines Original Article |
| Zdroj: | Acta Pharmacologica Sinica. 37:973-983 |
| ISSN: | 1745-7254 1671-4083 |
| DOI: | 10.1038/aps.2016.4 |
| Popis: | Urea transporters (UT) are a family of transmembrane proteins that specifically transport urea. UT inhibitors exert diuretic activity without affecting electrolyte balance. The purpose of this study was to discover novel UT inhibitors and determine the inhibition mechanism. The primary screening urea transporter B (UT-B) inhibitory activity was conducted in a collection of 10 000 diverse small molecules using mouse erythrocyte lysis assay. After discovering a hit with a core structure of 1-phenylamino-4-phenylphthalazin, the UT-B inhibitory activity of 160 analogs were examined with a stopped-flow light scattering assay and their structure-activity relationship (SAR) was analyzed. The inhibition mechanism was further investigated using in silico assays. A phenylphthalazine compound PU1424, chemically named 5-(4-((4-methoxyphenyl) amino) phthalazin-1-yl)-2-methylbenzene sulfonamide, showed potent UT-B inhibition activity, inhibited human and mouse UT-B-mediated urea transport with IC50 value of 0.02 and 0.69 μmol/L, respectively, and exerted 100% UT-B inhibition at higher concentrations. The compound PU1424 did not affect membrane urea transport in mouse erythrocytes lacking UT-B. Structure-activity analysis revealed that the analogs with methoxyl group at R4 and sulfonic amide at R2 position exhibited the highest potency inhibition activity on UT-B. Furthermore, in silico assays validated that the R4 and R2 positions of the analogs bound to the UT-B binding pocket and exerted inhibition activity on UT-B. The compound PU1424 is a novel inhibitor of both human and mouse UT-B with IC50 at submicromolar ranges. Its binding site is located at the So site of the UT-B structure. |
| Databáze: | OpenAIRE |
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