Computational protocol: Salt-sparing diuretic action of a water-soluble urea analog inhibitor of urea transporters UT-A and UT-B in rats

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Protocol publication

[…] A homology model of human UT-A1 was generated using the SWISS MODEL online utility (http://swissmodel.expasy.org) in automated mode, using the sequence of the full rat UT-A1 protein (accession code, NP_062220.2). The model was generated using coordinates from the X-ray crystal structure of bovine UT-B (PDB=4EZC, solved to 2.5 Å) () as a homology template. Additional processing of the model was carried out as reported previously (). The homology model was prepared for docking using the FRED-RECEPTOR utility (Version 2.2.5, OpenEye Scientific, Santa Fe, NM, http://www.eyesopen.com), with cytoplasmic and extracellular domains defined with 10 cubic Å boxes. Structures of DMTU and nicotine were drawn in ChemDraw (Cambridge Software, Cambridge, MA), converted to SMILES strings, transformed to three-dimensional conformations, and minimized using PIPELINE PILOT (Accelrys, San Diego, CA). The single conformations were passed through MOLCHARGE (Version 1.5.0, OpenEye Scientific) to apply MMFF charges, and through OMEGA (Version 2.4.6, OpenEye Scientific) to generate multi-conformational libraries. The inhibitor conformational libraries were docked using FRED (Version 2.2.5, OpenEye Scientific), which was configured to use consensus scoring functions ChemGauss3, ChemScore, OEChemScore, ScreenScore, ShapeGauss, PLP, and ZapBind. Docking of the inhibitors was carried out free of pharmacophore restraint. The final protein-inhibitor complexes were visualized using PYMOL (Schrödinger, San Diego, CA). […]

Pipeline specifications

Software tools SWISS-MODEL, ChemDraw, PyMOL
Databases ExPASy
Applications Drug design, Small-angle scattering, Protein structure analysis
Organisms Rattus norvegicus