MRP4/ABCC4 As a New Therapeutic Target: Meta-Analysis to Determine cAMP Binding Sites as a Tool for Drug Design
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Published:2019-05-14
Issue:7
Volume:26
Page:1270-1307
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ISSN:0929-8673
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Container-title:Current Medicinal Chemistry
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language:en
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Short-container-title:CMC
Author:
Yaneff Agustín1, Sahores Ana1, Gómez Natalia1, Carozzo Alejandro1, Shayo Carina2, Davio Carlos1
Affiliation:
1. Instituto de Investigaciones Farmacologicas (ININFA-UBA-CONICET), Facultad de Farmacia y Bioquimica, Universidad de Buenos Aires, Buenos Aires, Argentina 2. Instituto de Biologia y Medicina Experimental (IBYME-CONICET), Buenos Aires, Argentina
Abstract
MRP4 transports multiple endogenous and exogenous substances and is critical not only for detoxification but also in the homeostasis of several signaling molecules. Its dysregulation has been reported in numerous pathological disorders, thus MRP4 appears as an attractive therapeutic target. However, the efficacy of MRP4 inhibitors is still controversial. The design of specific pharmacological agents with the ability to selectively modulate the activity of this transporter or modify its affinity to certain substrates represents a challenge in current medicine and chemical biology. The first step in the long process of drug rational design is to identify the therapeutic target and characterize the mechanism by which it affects the given pathology. In order to develop a pharmacological agent with high specific activity, the second step is to systematically study the structure of the target and identify all the possible binding sites. Using available homology models and mutagenesis assays, in this review we recapitulate the up-to-date knowledge about MRP structure and aligned amino acid sequences to identify the candidate MRP4 residues where cyclic nucleotides bind. We have also listed the most relevant MRP inhibitors studied to date, considering drug safety and specificity for MRP4 in particular. This meta-analysis platform may serve as a basis for the future development of inhibitors of MRP4 cAMP specific transport.
Funder
Agencia Nacional de Promoción Científica y Tecnológica Universidad de Buenos Aires
Publisher
Bentham Science Publishers Ltd.
Subject
Pharmacology,Molecular Medicine,Drug Discovery,Biochemistry,Organic Chemistry
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