In silico drug repurposing at the cytoplasmic surface of human aquaporin 1
Aled R. Lloyd, Karl Austin-Muttitt, Jonathan G. L. Mullins
Abstract
Aquaporin 1 (AQP1) is a key channel for water transport in peritoneal dialysis. Inhibition of AQP1 could therefore impair water transport during peritoneal dialysis. It is not known whether inhibition of AQP1 occurs unintentionally due to off-target interactions of administered medications. A high-throughput virtual screening study has been performed to investigate the possible binding of licensed medications to the water pore of human AQP1. A complete model of human AQP1 based on its canonical sequence was assembled using I-TASSER and MODELLER.
Introduction
Aquaporin 1
Of the 13 human forms of aquaporin (AQP) identified to date, 8 can be found in the kidney (AQP1, AQP2, AQP3, AQP4, AQP5, AQP6, AQP7, and AQP11) [1]. Aquaporin was first identified serendipitously through investigation of a protein contaminating the process of purifying Rhesus proteins from erythrocytes [2]. This protein was found to be highly permeable to water and present in a wide range of plants, microbials, and animal species [2]. The 2003 Nobel prize for chemistry was awarded for this discovery [3]
Materials and method
Structural modelling
As portions of the cytoplasmic chains were incomplete in crystal structures and in order to create a model based solely on human sequences, threading modelling using the I-TASSER server and suite [34–36] was performed using the canonical FASTA sequence for AQP1 on the UniProt database(entry P29972-1) [37]. Structural visualisation and analysis were performed using UCSF Chimera software versions 1.16 and X1.2.5 [38]. Oligomerisation of the monomeric structure obtained from I-TASSER was performed by homology modelling using MODELLER [39].
Results
Structural data
Protein structure modelling and validation.
The canonical FASTA sequence for AQP1 obtained from the UniProt database (P29972-1) was used to obtain I-TASSER structures for AQP1, with a C-score of 1.05 for the best matched model [34, 35, 37]. The initial monomeric and tetrameric structures of AQP1 showed very good visual semblance with published crystal structures for human forms of AQP1. The matchmaker function of USCF Chimera was used to calculate the root mean square deviation (RMSD) of alpha-carbon positions between the experimental model and a monomeric human AQP1 structure from the Protein Data Bank (PDB 3CSK) [56].
Discussion
The potential clinical applications of AQP inhibition include treating conditions such as volume overload related to cardiac or renal dysfunction, the treatment of glaucoma or macular oedema and even potentially cerebral oedema due to stroke [20]. As a result there is an emerging effort to identify inhibitors at scale [63]. In contrast to other studies, this work has focussed on existing licensed medication, and aims to investigate the possibility that some adverse effects could be explained by identifying an off-target interaction between the drug and AQP1. There are circumstances where AQP1 inhibition would be undesirable, such as in peritoneal dialysis, where AQP1 activity is thought to play a prominent role [19].
Conclusion
Traditionally aquaporins have not been considered drug targets, however off-target inhibition of AQP1 could impede peritoneal dialysis efficiency. Loop diuretics are known to interact with the cytoplasmic surface of AQP1 causing inhibition and in this work, this region has been subject to a computational screening study aiming to identify other licensed drug compounds capable of a similar interaction.
Citation: Lloyd AR, Austin-Muttitt K, Mullins JGL (2025) In silico drug repurposing at the cytoplasmic surface of human aquaporin 1. PLoS ONE 20(1): e0314151. https://doi.org/10.1371/journal.pone.0314151
Editor: Bijay Kumar Behera, Rani Lakshmi Bai Central Agricultural University, INDIA
Received: August 14, 2024; Accepted: November 5, 2024; Published: January 9, 2025
Copyright: © 2025 Lloyd et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All docking results and molecular dynamics files for this study are available from the figshare database. The relevant DOI numbers are 10.6084/m9.figshare.27312210.v1, https://doi.org/10.6084/m9.figshare.27312189.v1, 10.6084/m9.figshare.27312174.v1, 10.6084/m9.figshare.27312168.v1, and 10.6084/m9.figshare.27312147.v1.
Funding: The author(s) received no specific funding for this work.
Competing interests: The authors have declared that no competing interests exist.
