ABSTRACT
The human genome encodes 13 aquaporin isoforms with characteristic substrate speci-city that are expressed at specic locations throughout the body. Of these isoforms, AQPs 1-4 serve important functions in renal water reabsorption. Consequently, specic AQP inhibitors have been proposed as ‘aquaretics’, a new class of drugs suitable to induce
CONTENTS Abstract 249 13.1 Introduction 250 13.2AQPs as erapeutic Targets 251
13.2.1 Oncology 251 13.2.2Kidney Diseases 252 13.2.3 Glaucoma 253 13.2.4Osmotic Disequilibrium Pathologies of the Brain 254 13.2.5AQPs in Diabetes and Obesity 255 13.2.6Disuse Osteoporosis 256 13.2.7AQP Inhibitors as Immunosuppressants 256 13.2.8Medical Imaging 257
13.3Methods for AQP Inhibitor Identication 257 13.3.1Xenopus laevis Oocyte Assay 257 13.3.2Proteoliposome Assays 258 13.3.3Calcein Quenching Assays 258 13.3.4End Point Hypotonic Shock Assays 259
13.4In Silico Methods for AQP Inhibitor Optimization (and Potentially Ab Initio Identication) 259 13.4.1Molecular Docking 259 13.4.2Molecular Dynamics Simulations 262
13.5 Conclusions 263 References 263
diuresis without concomitant salt wasting. Furthermore, animal experiments suggested that AQP4 inhibitors could be useful to treat some forms of brain edema. Other proposed applications for AQP inhibitors involve amongst others treatment of diabetes, inammatory skin diseases and cancer. However, few of these putative applications have been critically evaluated against current forms of therapy. Furthermore, development of AQP inhibitors remains di cult and despite numerous eorts during at least the last 15 years very few AQP inhibitors have been described. Moreover, none of the hitherto described substances have been developed to a level where meaningful verication of proposed AQP drug targets in preclinical or clinical settings was possible. Nonetheless, encouraging progress towards development of such substances has been made during recent years. Novel cell-based assays facilitate high throughput screening of chemical compound libraries for hit discovery. AQP 3D structures have been solved for 10 isoforms, which can support rapidly evolving computational hit discovery methods, as well as hit to lead programs. In this chapter, we will provide a critical review of current evidence supporting relevance of AQPs as drug targets, describe current methods for AQP inhibitor discovery and will try to highlight challenges that remain before successful AQP inhibitor development.
