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Macrocycles in Drug Discovery—Learning from the Past for the Future
[Image: see text] We have analyzed FDA-approved macrocyclic drugs, clinical candidates, and the recent literature to understand how macrocycles are used in drug discovery. Current drugs are mainly used in infectious disease and oncology, while oncology is the major indication for the clinical candid...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Chemical Society
2023
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10150360/ https://www.ncbi.nlm.nih.gov/pubmed/37017513 http://dx.doi.org/10.1021/acs.jmedchem.3c00134 |
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author | Garcia Jimenez, Diego Poongavanam, Vasanthanathan Kihlberg, Jan |
author_facet | Garcia Jimenez, Diego Poongavanam, Vasanthanathan Kihlberg, Jan |
author_sort | Garcia Jimenez, Diego |
collection | PubMed |
description | [Image: see text] We have analyzed FDA-approved macrocyclic drugs, clinical candidates, and the recent literature to understand how macrocycles are used in drug discovery. Current drugs are mainly used in infectious disease and oncology, while oncology is the major indication for the clinical candidates and in the literature Most macrocyclic drugs bind to targets that have difficult to drug binding sites. Natural products have provided 80–90% of the drugs and clinical candidates, whereas macrocycles in ChEMBL have less complex structures. Macrocycles usually reside in the beyond the Rule of 5 chemical space, but 30–40% of the drugs and clinical candidates are orally bioavailable. Simple bi-descriptor models, i.e., HBD ≤ 7 in combination with either MW < 1000 Da or cLogP > 2.5, distinguished orals from parenterals and can be used as filters in design. We propose that recent breakthroughs in conformational analysis and inspiration from natural products will further improve the de novo design of macrocycles. |
format | Online Article Text |
id | pubmed-10150360 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | American Chemical Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-101503602023-05-02 Macrocycles in Drug Discovery—Learning from the Past for the Future Garcia Jimenez, Diego Poongavanam, Vasanthanathan Kihlberg, Jan J Med Chem [Image: see text] We have analyzed FDA-approved macrocyclic drugs, clinical candidates, and the recent literature to understand how macrocycles are used in drug discovery. Current drugs are mainly used in infectious disease and oncology, while oncology is the major indication for the clinical candidates and in the literature Most macrocyclic drugs bind to targets that have difficult to drug binding sites. Natural products have provided 80–90% of the drugs and clinical candidates, whereas macrocycles in ChEMBL have less complex structures. Macrocycles usually reside in the beyond the Rule of 5 chemical space, but 30–40% of the drugs and clinical candidates are orally bioavailable. Simple bi-descriptor models, i.e., HBD ≤ 7 in combination with either MW < 1000 Da or cLogP > 2.5, distinguished orals from parenterals and can be used as filters in design. We propose that recent breakthroughs in conformational analysis and inspiration from natural products will further improve the de novo design of macrocycles. American Chemical Society 2023-04-05 /pmc/articles/PMC10150360/ /pubmed/37017513 http://dx.doi.org/10.1021/acs.jmedchem.3c00134 Text en © 2023 The Authors. Published by American Chemical Society https://creativecommons.org/licenses/by/4.0/Permits the broadest form of re-use including for commercial purposes, provided that author attribution and integrity are maintained (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Garcia Jimenez, Diego Poongavanam, Vasanthanathan Kihlberg, Jan Macrocycles in Drug Discovery—Learning from the Past for the Future |
title | Macrocycles
in
Drug Discovery—Learning from
the Past for the Future |
title_full | Macrocycles
in
Drug Discovery—Learning from
the Past for the Future |
title_fullStr | Macrocycles
in
Drug Discovery—Learning from
the Past for the Future |
title_full_unstemmed | Macrocycles
in
Drug Discovery—Learning from
the Past for the Future |
title_short | Macrocycles
in
Drug Discovery—Learning from
the Past for the Future |
title_sort | macrocycles
in
drug discovery—learning from
the past for the future |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10150360/ https://www.ncbi.nlm.nih.gov/pubmed/37017513 http://dx.doi.org/10.1021/acs.jmedchem.3c00134 |
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