title: 1,3-Propanediol binds inside the water-conducting pore of aquaporin 4: Does this efficacious inhibitor have sufficient potency?
abstract: Among the thirteen types of water channel proteins, aquaporins (AQPs), which play various essential roles in human physiology, AQP4 is richly expressed in cells of the central nervous system and implicated in pathological conditions such as brain edema. Therefore, researchers have been looking for ways to inhibit AQP4's water-conducting function. Many small molecules have been investigated for their interactions with the residues that form the AQP4 channel entry vestibule on the extracellular side and their interruption of waters entering into the conducting pore. Conducting all-atom simulations on the basis of CHARMM 36 force field, we study one such inhibitor, 5-acetamido-1,3,4-thiadiazole-2-sulfonamide (AZM), to achieve quantitative agreement between the computed and the experimentally measured values of AZM-AQP4 binding affinity. Using the same method, we examine the possibility of plugging up the AQP4 channel around the Asn-Pro-Ala motifs located near the channel center because a small molecule bound there would totally occlude water conduction through AQP4. We compute the binding affinities of 1,2-ethanediol (EDO) and 1,3-propanediol (PDO) inside the AQP4 conducting pore and identify the specificities of the interactions. The EDO-AQP4 interaction is weak with a dissociation constant of 80 mM. The PDO-AQP4 interaction is rather strong with a dissociation constant of 328 μM, which indicates that PDO is an efficacious AQP4 inhibitor with sufficiently high potency. Considering the fact that PDO is classified by the US Food and Drug Administration as generally safe, we predict that 1,3-propanediol could be an effective drug for brain edema and other AQP4-correlated neurological conditions.
authors.affiliation: Department of Physics, University of Texas at San Antonio, San Antonio, Texas 78249, USA.
authors.forename: Lili
authors.initials: L
authors.lastname: Yu
authors.affiliation: Department of Physics, University of Texas at San Antonio, San Antonio, Texas 78249, USA.
authors.forename: Oscar D
authors.initials: OD
authors.lastname: Villarreal
authors.affiliation: Medical School, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: L Laurie
authors.initials: LL
authors.lastname: Chen
authors.affiliation: Department of Physics, University of Texas at San Antonio, San Antonio, Texas 78249, USA.
authors.forename: Liao Y
authors.initials: LY
authors.lastname: Chen
keywords: aquaporin inhibitor; ligand-protein interaction; molecular dynamics