Structural Features Affecting the Interactions and Transportability of LAT1-Targeted Phenylalanine Drug Conjugates
| العنوان: | Structural Features Affecting the Interactions and Transportability of LAT1-Targeted Phenylalanine Drug Conjugates |
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| المؤلفون: | Katayun Bahrami, Juulia Järvinen, Tuomo Laitinen, Mika Reinisalo, Paavo Honkakoski, Antti Poso, Kristiina M. Huttunen, Jarkko Rautio |
| المصدر: | Molecular Pharmaceutics. 20:206-218 |
| بيانات النشر: | American Chemical Society (ACS), 2022. |
| سنة النشر: | 2022 |
| مصطلحات موضوعية: | Drug Delivery Systems, Blood-Brain Barrier, Phenylalanine, Drug Discovery, Pharmaceutical Science, Molecular Medicine, Prodrugs, Biological Transport, Amino Acids |
| الوصف: | L-type amino acid transporter 1 (LAT1) transfers essential amino acids across cell membranes. Owing to its predominant expression in the blood-brain barrier and tumor cells, LAT1 has been exploited for drug delivery and targeting to the central nervous system (CNS) and various cancers. Although the interactions of amino acids and their mimicking compounds with LAT1 have been extensively investigated, the specific structural features for an optimal drug scaffold have not yet been determined. Here, we evaluated a series of LAT1-targeted drug-phenylalanine conjugates (ligands) by determining their uptake rates by in vitro studies and investigating their interaction with LAT1 via induced-fit docking. Combining the experimental and computational data, we concluded that although LAT1 can accommodate various types of structures, smaller compounds are preferred. As the ligand size increased, its flexibility became more crucial in determining the compound's transportability and interactions. Compounds with linear or planar structures exhibited reduced uptake; those with rigid lipophilic structures lacked interactions and likely utilized other transport mechanisms for cellular entry. Introducing polar groups between aromatic structures enhanced interactions. Interestingly, compounds with a carbamate bond in the aromatic ring's para-position displayed very good transport efficiencies for the larger compounds. Compared to the ester bond, the corresponding amide bond had superior hydrogen bond acceptor properties and increased interactions. A reverse amide bond was less favorable than a direct amide bond for interactions with LAT1. The present information can be applied broadly to design appropriate CNS or antineoplastic drug candidates with a prodrug strategy and to discover novel LAT1 inhibitors used either as direct or adjuvant cancer therapy. |
| تدمد: | 1543-8392 1543-8384 |
| DOI: | 10.1021/acs.molpharmaceut.2c00594 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::c3bc3c3e2892be8ef3d43334e6ffd537 https://doi.org/10.1021/acs.molpharmaceut.2c00594 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....c3bc3c3e2892be8ef3d43334e6ffd537 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15438392 15438384 |
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| DOI: | 10.1021/acs.molpharmaceut.2c00594 |