1,3-propanediol binds deep inside the channel to inhibit water permeation through aquaporins.
Aquaporins and aquaglyceroporins (AQPs) are membrane channel proteins responsible for transport of water and for transport of glycerol in addition to water across the cell membrane, respectively. They are expressed throughout the human body and also in other forms of life. Inhibitors of human AQPs have been sought for therapeutic treatment for various medical conditions including hypertension, refractory edema, neurotoxic brain edema, and so forth. Conducting all-atom molecular dynamics simulations, we computed the binding affinity of acetazolamide to human AQP4 that agrees closely with in vitro experiments. Using this validated computational method, we found that 1,3-propanediol (PDO) binds deep inside the AQP4 channel to inhibit that particular aquaporin efficaciously. Furthermore, we used the same method to compute the affinities of PDO binding to four other AQPs and one aquaglyceroporin whose atomic coordinates are available from the protein data bank (PDB). For bovine AQP1, human AQP2, AQP4, AQP5, and Plasmodium falciparum PfAQP whose structures were resolved with high resolution, we obtained definitive predictions on the PDO dissociation constant. For human AQP1 whose PDB coordinates are less accurate, we estimated the dissociation constant with a rather large error bar. Taking into account the fact that PDO is generally recognized as safe by the US FDA, we predict that PDO can be an effective diuretic which directly modulates water flow through the protein channels. It should be free from the serious side effects associated with other diuretics that change the hydro-homeostasis indirectly by altering the osmotic gradients.
Department of Physics, University of Texas at San Antonio, San Antonio, Texas, 78249.
Lili
L
Yu
Department of Physics, University of Texas at San Antonio, San Antonio, Texas, 78249.
Roberto A
RA
Rodriguez
Medical School, University of Texas Southwestern Medical Center, Dallas, Texas, 75390.
L Laurie
LL
Chen
Department of Physics, University of Texas at San Antonio, San Antonio, Texas, 78249.
Liao Y
LY
Chen
Department of Biology, University of Texas at San Antonio, San Antonio, Texas, 78249.
George
G
Perry
Department of Chemistry, University of Texas at San Antonio, San Antonio, Texas, 78249.
Stanton F
SF
McHardy
Department of Comprehensive Dentistry, University of Texas Health Science Center at San Antonio & GRECC, South Texas Veterans Health Care System, San Antonio, Texas 78229.
Chih-Ko
CK
Yeh
D000818:Animals; D020346:Aquaporins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D001692:Biological Transport / Q000187:drug effects; D002417:Cattle; D006801:Humans; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D010539:Permeability / Q000187:drug effects; D010963:Plasmodium falciparum / Q000378:metabolism; D011409:Propylene Glycols / Q000378:metabolism / Q000494:pharmacology*; D011485:Protein Binding; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D014867:Water / Q000378:metabolism*
D020346:Aquaporins; D011409:Propylene Glycols; D015800:Protozoan Proteins; D014867:Water; C041787:1,3-propanediol
aquaporin inhibitor; ligand-protein interaction; molecular dynamics