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.

Computing osmotic permeabilities of aquaporins AQP4, AQP5, and GlpF from near-equilibrium simulations

“…[4, 16–34] on GlpF and AQPZ expressed in E. coli , Refs. [8, 35–77] on AQP4, and Refs. [38, 70, 78–86] on AQP5.…”

Cryotolerance of Stallion Spermatozoa Relies on Aquaglyceroporins rather than Orthodox Aquaporins

“…Taking this into account, this study aimed to unveil the relevance of each group of AQPs during stallion sperm cryopreservation. With this purpose, three different inhibitors were added at different concentrations: AC, which is known to inhibit AQP1 and AQP4 [40,41]; PHL, which inhibits both AQP3 and AQP7 [42][43][44]; PDO, which has been proven to inhibit orthodox AQPs (AQP1, AQP2, AQP5 and AQP4) with high efficiency; and GLPs (the family to which AQP3, AQP7 and AQP9 belong) with low intensity [45,46]. The effects of each AQP-inhibitor on sperm function and survival after cryopreservation were assessed on the basis of sperm motility, sperm viability, acrosome integrity, membrane lipid disorder, MMP, intracellular calcium levels, and intracellular levels of ROS.…”

“…Regarding PDO, it strongly inhibits orthodox the AQPs remaining inside their pore [45,46]. PDO also inhibits GLPs, though less efficiently, since the pore diameter of GLPs is broader than that of orthodox AQPs.…”

Effect of AQP Inhibition on Boar Sperm Cryotolerance Depends on the Intrinsic Freezability of the Ejaculate

“…To this end, two inhibitors were added to the extender at three different concentrations: PDO at 0.1, 1 and 10 mmol/L, and PHL at 250, 500, and 1000 µmol/L. Whereas PDO inhibits orthodox AQPs (AQP1, AQP2, AQP5, and AQP4) with high efficiency, it is less efficient as a GLPs inhibitor (the family to which AQP3, AQP7, and AQP9 belong) is lower [28,29]. PHL, on the other hand, inhibits both AQP3 and AQP7 [32][33][34].…”

“…Different AQP inhibitors have been previously tested in other cell types, such as 1,3-propanediol (PDO) and phloretin (PHL). PDO has been proven to occlude, with high affinity, the pore channel of orthodox AQPs from the outer side of the plasma membrane and with high affinity [28,29]. In addition, PDO is able to penetrate through Plasmodium falciparum Pf AQP (which is an analogue of AQP3, AQP7, and AQP9) and to mildly inhibit this GLP analogue from the inner part of the plasma membrane [28].…”