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Review
, 40 (10), 790-800

Advances and Challenges in Rational Drug Design for SLCs

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Review

Advances and Challenges in Rational Drug Design for SLCs

Rachel-Ann A Garibsingh et al. Trends Pharmacol Sci.

Abstract

There are over 420 human solute carrier (SLC) transporters from 65 families that are expressed ubiquitously in the body. The SLCs mediate the movement of ions, drugs, and metabolites across membranes and their dysfunction has been associated with a variety of diseases, such as diabetes, cancer, and central nervous system (CNS) disorders. Thus, SLCs are emerging as important targets for therapeutic intervention. Recent technological advances in experimental and computational biology allow better characterization of SLC pharmacology. Here we describe recent approaches to modulate SLC transporter function, with an emphasis on the use of computational approaches and computer-aided drug design (CADD) to study nutrient transporters. Finally, we discuss future perspectives in the rational design of SLC drugs.

Keywords: computer-aided drug design; membrane transporter; protein structure prediction; solute carrier; structure-based drug discovery.

Figures

Figure 1.
Figure 1.. Different SLC alternating access transport mechanisms.
(A) For each transport mechanism, there is a representative schematic of an unbound outward-open conformation that is accessible to both inhibitor and substrate, an occluded inhibitor bound state, representative of when inhibitor binding blocks substrate transport and an inward open conformation, which is accessible to substrate from the intracellular side of the membrane. The colors denote the two different domains involved in the mechanism. The figure only shows one protomer even if more than one subunit is involved. The rocker-switch mechanism, the substrate binds to the extracellular facing binding site, triggering conformational changes to an occluded state, followed by an inward-facing state where the substrate is released. Rocking bundle or gated-pore mechanism has a mobile bundle domain (in orange) that undergoes large hinge-like rearrangements to release the substrate to the intracellular side, while the scaffold domain (in cyan) remains static. The elevator mechanism has a mobile domain (pink) that moves up and down, relative to a scaffold domain (gray), to transport the substrate across the membrane. (B) Representative structures of transporters using the transport mechanisms in (A) where the colors correspond to the respective domains as shown in (A), substrate binding site and allosteric site inhibitors are shown in yellow and red spheres, respectively. PDB IDs: GLUT1: 4PYP, SERT: 5I73, EAAT1: 5LLM.
Figure 2.
Figure 2.. Substrate and allosteric binding sites of EAAT1 and ASCT2.
Here, gray represents the scaffold domain and; dark blue hairpins 1 and 2 (HP1 and 2) and pink comprise the transport domain. The substrate and allosteric binding sites of EAAT1 (PDB ID: 5MJU) are shown in gray and cyan spheres respectively. Here, dotted lines show the approximate location of the membrane. Inset left: Surface representations of the substrate binding site of the outward-open conformation for ASCT2 and EAAT1. Pockets A and B (PA and PB) are highlighted and residues impacting substrate specificity and binding site shape are shown as sticks with oxygen, nitrogen, and sulfur atoms shown in red, blue, and yellow. Inset right: The allosteric inhibitor UCPH101 bound to EAAT1. Key residues making polar contacts with UCPH101 are highlighted as orange sticks. Images were generated with PyMOL (https://pymol.org/2/).
Fig. 3.
Fig. 3.. Structure of an ADME transporter homolog, PepTSh.
The crystal structure of PepTSh (green cartoon) in complex with the antiviral drug valacyclovir (peach sticks) is shown. The substrate binding site is shown in light blue mesh. Inset shows the magnified view of the interaction of valacycolovir with the binding site of PepSh. The sidechain atoms of key residues in PepTSh are illustrated with cyan sticks, with Y40, in yellow. Y40 is equivalent to F28 in the human PepT1. Rare mutation in this position in African Americans (F28Y) reduces substrate uptake by PepT1. Hydrogen bonds between binding site residues and valacycolvir are displayed as dashed gray lines. Images were generated with PyMOL (https://pymol.org/2/).

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