Aquaporins (AQPs) are a family of 13 small integral membrane proteins, whose primary function is to facilitate the passive transport of water across the plasma membrane of the cell, in response to osmotic gradients created by the active transport of solutes. These small membrane-spanning proteins assemble as homotetramers in which each monomer is composed by an extracellular and cytoplasmic vestibule connected by a central amphipathic pore region in a barrel like arrangement. 
These proteins are widely expressed throughout the animal and plant kingdom, being localized in the plasma membrane and in the cytoplasmic compartments, particularly in cell types that are involved in fluid transport. AQPs have been proven to play key roles in tumor biology, including histological tumor grade, proliferation, migration, angiogenesis, or tumor-associated edema, namely due to its over-expression when compared to normal tissues. Therefore, AQPs can work as potential diagnostic and therapeutic targets in anticancer treatment, since their inhibition in endothelial and tumor cells might limit tumor growth and spread.  Unfortunately, the hit rate for the identification of small-molecule AQP modulators appears to be very low when compared to other membrane proteins, and the few available pharmacological modulators lack specificity or show high toxicity.  One of the possible explanations for this low druggability is the small size of the functional AQP monomer and its small pore diameter. Nonetheless, the continuous growing of structure/function knowledge on AQPs, particularly the atomic-level geometry of specific hydrophobic and hydrophilic residues in the pore region, makes AQPs a promising therapeutic target to be used in future computational drug discovery campaigns.  However, in order to achieve successful results, new and innovative approaches and methods must also be developed. Consequently, we are currently developing a new computational workflow based on several distinct methods that combine innovative ligand and structure-based approaches to identify new AQP modulators. In this work, we will present the first steps of the developed protocol, focusing our studies on AQP – subtype 1.
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 Wang, J., Feng, L., Zhu, Z., Zheng, M., Wang, D., Chen, Z., & Sun, H. (2015). Aquaporins as diagnostic and therapeutic targets in cancer: How far we are? Journal of Translational Medicine, 13(96).
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