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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...

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Autores principales: Garcia Jimenez, Diego, Poongavanam, Vasanthanathan, Kihlberg, Jan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2023
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.
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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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