Targeting SLC transporters: small molecules as modulators and therapeutic opportunities

Schlessinger, Avner; Zatorski, Nicole; Hutchinson, Keino; Colas, Claire

doi:10.1016/j.tibs.2023.05.011

Cited by 24 publications

(27 citation statements)

References 115 publications

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“…10 Meanwhile, the inhibition of certain SLCs could provide the rationale strategy treatment for these various diseases. 6 The ligand binding sites on SLCs and the natural interaction substrates are considered to be the most valuable information for novel drug design. It is also mentioned that the selectivity of the inhibitor among transporters may directedly pose effects on therapeutic intervention of diseases associated with transporter dysfunction.…”

Section: ■ Drug Design Targeting Slcsmentioning

confidence: 99%

“…Allosteric modulation is an attractive strategy to SLCs to inhibit or enhance their function. 6 Allosteric inhibitors are capable of binding to target-specific pockets with high selectivity. For SERT, these allosteric binding sites and allosteric inhibitor binding modes have made great strides forward with the help of advanced computational and experimental methods.…”

Section: ■ Drug Design Targeting Slcsmentioning

confidence: 99%

“…118 In the transport cycle, transporters undergo highly diverse conformational changes, adopting a conserved "alternating access" transport mechanism, in which transporters switch from the outward-open conformation to the inward-open conformation. 6 For SERT, the cryo-EM structures in the outward-open, outwardoccluded, and inward-open conformations have been reported (Figure 2), which provide insight into the transport cycle of neurotransmitters. 48 Currently, many studies have been devoted to the transport mechanisms of SLCs with the expectation of facilitating drug discovery and disease treatment.…”

mentioning

confidence: 99%

“…In addition, Schlessinger et al systematically analyzed the pharmacological space of 52 SLC families based on chemical similarity of their small molecule ligands using the ChEMBL database. 6 It is found that except for small subsets of SLCs drugs that show significant bias for well-connected members, such as monoamine transporters (DAT, NET, and SERT) and sugar transporters (SGLT1 and GLUT1), the majority of SLCs are highly diverse and unrelated in structure evolution, which is a great challenge in structure-based transporter drug design. Therefore, it is urgent to explore the mutations' effects on the structure and function SLCs, and we can gain a better understanding of mechanism of diseases (see details in the Structure and Function of SLCs section), which is important to structure-based discovery of novel drugs for new treatments in the future.…”

mentioning

confidence: 99%

“…20,39 On one hand, inhibitors targeting specific conformations lead to compounds with better in vivo efficacy, further refining our understanding of pharmacological control of transporter function. 6 On the other hand, allosteric mechanisms can also be successfully identified based on multiple conformations of MATs. 20 There are still many questions about the transport cycle that have not yet been elucidated, including the transport dynamics at the atomic level, energy coupling, and regulatory mechanism.…”

mentioning

confidence: 99%

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Computational Chemistry in Structure-Based Solute Carrier Transporter Drug Design: Recent Advances and Future Perspectives

Tu,

Fu,

Zheng

et al. 2024

J. Chem. Inf. Model.

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Solute carrier transporters (SLCs) are a class of important transmembrane proteins that are involved in the transportation of diverse solute ions and small molecules into cells. There are approximately 450 SLCs within the human body, and more than a quarter of them are emerging as attractive therapeutic targets for multiple complex diseases, e.g., depression, cancer, and diabetes. However, only 44 unique transporters (∼9.8% of the SLC superfamily) with 3D structures and specific binding sites have been reported. To design innovative and effective drugs targeting diverse SLCs, there are a number of obstacles that need to be overcome. However, computational chemistry, including physics-based molecular modeling and machine learning-and deep learning-based artificial intelligence (AI), provides an alternative and complementary way to the classical drug discovery approach. Here, we present a comprehensive overview on recent advances and existing challenges of the computational techniques in structure-based drug design of SLCs from three main aspects: (i) characterizing multiple conformations of the proteins during the functional process of transportation, (ii) identifying druggability sites especially the cryptic allosteric ones on the transporters for substrates and drugs binding, and (iii) discovering diverse small molecules or synthetic protein binders targeting the binding sites. This work is expected to provide guidelines for a deep understanding of the structure and function of the SLC superfamily to facilitate rational design of novel modulators of the transporters with the aid of state-of-the-art computational chemistry technologies including artificial intelligence.

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Section: ■ Drug Design Targeting Slcsmentioning

confidence: 99%

Section: ■ Drug Design Targeting Slcsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Computational Chemistry in Structure-Based Solute Carrier Transporter Drug Design: Recent Advances and Future Perspectives

Tu,

Fu,

Zheng

et al. 2024

J. Chem. Inf. Model.

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The macrocycle inhibitor landscape of SLC‐transporter

Granulo,

Sosnin,

Digles

et al. 2024

Molecular Informatics

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In the past years the interest in Solute Carrier Transporters (SLC) has increased due to their potential as drug targets. At the same time, macrocycles demonstrated promising activities as therapeutic agents. However, the overall macrocycle/SLC‐transporter interaction landscape has not been fully revealed yet. In this study, we present a statistical analysis of macrocycles with measured activity against SLC‐transporter. Using a data mining pipeline based on KNIME retrieved in total 825 bioactivity data points of macrocycles interacting with SLC‐transporter. For further analysis of the SLC inhibitor profiles we developed an interactive KNIME workflow as well as an interactive map of the chemical space coverage utilizing parametric t‐SNE models. The parametric t‐SNE models provide a good discrimination ability among several corresponding SLC subfamilies’ targets. The KNIME workflow, the dataset, and the visualization tool are freely available to the community.

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Spatiotemporal modeling of chemoresistance evolution in breast tumors uncovers dependencies on SLC38A7 and SLC46A1

Audet-Delage,

St-Louis,

Minarrieta

et al. 2023

Cell Reports

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Targeting SLC transporters: small molecules as modulators and therapeutic opportunities

Cited by 24 publications

References 115 publications

Computational Chemistry in Structure-Based Solute Carrier Transporter Drug Design: Recent Advances and Future Perspectives

Computational Chemistry in Structure-Based Solute Carrier Transporter Drug Design: Recent Advances and Future Perspectives

The macrocycle inhibitor landscape of SLC‐transporter

Spatiotemporal modeling of chemoresistance evolution in breast tumors uncovers dependencies on SLC38A7 and SLC46A1

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