Homology Modeling of Human c-Butyric Acid Transporters and the Binding of Pro-Drugs 5-Aminolevulinic Acid and Methyl Aminolevulinic Acid Used in Photodynamic Therapy
2013 (English)In: PLoS ONE, ISSN 1932-6203, Vol. 8, no 6, e65200- p.Article in journal (Refereed) Published
Photodynamic therapy (PDT) is a safe and effective method currently used in the treatment of skin cancer. In ALA-basedPDT, 5-aminolevulinic acid (ALA), or ALA esters, are used as pro-drugs to induce the formation of the potent photosensitizerprotoporphyrin IX (PpIX). Activation of PpIX by light causes the formation of reactive oxygen species (ROS) and toxicresponses. Studies have indicated that ALA and its methyl ester (MAL) are taken up into the cells via c-butyric acid (GABA)transporters (GATs). Uptake via GATs into peripheral sensory nerve endings may also account for one of the few adverseside effects of ALA-based PDT, namely pain. In the present study, homology models of the four human GAT subtypes wereconstructed using three x-ray crystal structures of the homologous leucine transporter (LeuT) as templates. Binding of thenative substrate GABA and the possible substrates ALA and MAL was investigated by molecular docking of the ligands intothe central putative substrate binding sites in the outward-occluded GAT models. Electrostatic potentials (ESPs) of theputative substrate translocation pathway of each subtype were calculated using the outward-open and inward-openhomology models. Our results suggested that ALA is a substrate of all four GATs and that MAL is a substrate of GAT-2, GAT-3and BGT-1. The ESP calculations indicated that differences likely exist in the entry pathway of the transporters (i.e. inoutward-open conformations). Such differences may be exploited for development of inhibitors that selectively targetspecific GAT subtypes and the homology models may hence provide tools for design of therapeutic inhibitors that can beused to reduce ALA-induced pain.
Place, publisher, year, edition, pages
2013. Vol. 8, no 6, e65200- p.
IdentifiersURN: urn:nbn:no:ntnu:diva-24820DOI: 10.1371/journal.pone.0065200OAI: oai:DiVA.org:ntnu-24820DiVA: diva2:721754
©2013 Baglo et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.2014-06-042014-06-042014-07-08Bibliographically approved