Docking-MD Polypharmacy Screening Study of Loop D of Human Aquaporin 1

Background: The arginine rich Loop D of aquaporin 1 (AQP1) as the putative cGMP binding site, has been implicated in cation transport, water transport regulation, tumour cell angiogenesis and tumour cell migration. We have performed a computational screen of licensed compounds using docking and molecular dynamics (MD) methodologies to identify compounds capable of interacting with this region. Methods: I-TASSER and MODELLER were used to build a complete model of human AQP1. This underwent membrane bound MD equilibration using CHARMM-GUI and the GROMACS-on-Colab platform. Docking studies using the polypharmacy300 library were conducted and analysed using AutoDock Vina and the tools available at proteins.swan.ac.uk/modelling-portal. Three simulations of 10 nanosecond duration to assess the stability of the best performing docked conformations were undertaken using GROMACS-on-Colab. Results: Of the 268 compounds assessed, docked poses were obtained for 231. By filtering these results for compounds with the best 20% calculated binding energies and at least 2 hydrogen bonds to residues 161-169, 9 compounds were selected for MD investigation. Of these, 7 compounds remained bound during MD simulations. The best performing compounds were famotidine, carbidopa, lisinopril and bendroflumethiazide. Conclusion: These compounds appear capable of interacting with loop D of AQP1, excluding cGMP and keeping the central pore in a closed position. The results necessitate experimental validation but could represent new adjunctive options in the treatment of some cancers and compounds to avoid in peritoneal dialysis.The best docked position of famotidine (A), carbidopa (B), lisinopril (C), and bendroflumethiazide (D) with loop D of human AQP1.