Polypharmacy Screen of the Thiazide-Sensitive Sodium Chloride Cotransporter (NCC)

Background: The sodium chloride cotransporter (NCC) plays an important role in salt and water retention and is targeted in the treatment of hypertension and oedema. The site of NCC inhibition by polythiazide has been identified. This study describes a computational screening experiment using docking and molecular dynamics studies aimed at identifying licensed medicinal compounds that may have a similar action to thiazide compounds. Methods: A complete dimeric NCC model was obtained using the MODELLER based homology modelling tools at proteins.swan.ac.uk/modelling-portal using canonical sequence on the UniProt database for NCC (P55017) and PDB structure 8FHO as a scaffold. A 5 nanosecond membrane-bound MD simulation was run on the GROMACS-on-Colab platform to prepare the model for docking studies. The PLANTS ChemPLP scoring system provided the closest match on re-docking a reference compound and was used for the main screening study. The library of compounds for this study was the active agent list of the polypharmacy300 library. The stability of the best performing docked conformations was assessed using the median root mean square deviation values obtained from three10 nanosecond MD simulations. Results: In total 229 docked conformations were obtained from the 263 compounds in the library. These results were filtered by hydrogen bonding pattern, key residue overlap and clinical indication. 10 compounds were selected for further study: atenolol, furosemide, bendroflumethiazide, dapagliflozin, empagliflozin, labetalol, ramiprilat, metolazone, amlodipine and indapamide. All compounds remained bound during MD simulations. The lowest RMSD values were observed for indapamide, metolazone, dapagliflozin, furosemide and empagliflozin. Conclusion: Potentially significant interactions between the site of known NCC inhibition and three compounds known to exert diuretic effects (dapagliflozin, empagliflozin and furosemide) have been identified in this computational screening study.A selection of docked conformations from a virtual polypharmacy screen of NCC.