Data-Driven Analysis of Fluorination of Ligands of Aminergic G Protein Coupled Receptors

Currently, G protein-coupled receptors are the targets with the highest number of drugs in many therapeutic areas. Fluorination has become a common strategy in designing highly active biological compounds, as evidenced by the steadily increasing number of newly approved fluorine-containing drugs. He...

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Autores principales:	Wojciech Pietruś, Rafał Kurczab, Dagmar Stumpfe, Andrzej J. Bojarski, Jürgen Bajorath
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	G protein-coupled receptors GPCR aminergic receptors fluorine activity cliffs MMP Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/cd62e2b920104ecb91d770b5e194e417
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spelling	oai:doaj.org-article:cd62e2b920104ecb91d770b5e194e4172021-11-25T16:53:21ZData-Driven Analysis of Fluorination of Ligands of Aminergic G Protein Coupled Receptors10.3390/biom111116472218-273Xhttps://doaj.org/article/cd62e2b920104ecb91d770b5e194e4172021-11-01T00:00:00Zhttps://www.mdpi.com/2218-273X/11/11/1647https://doaj.org/toc/2218-273XCurrently, G protein-coupled receptors are the targets with the highest number of drugs in many therapeutic areas. Fluorination has become a common strategy in designing highly active biological compounds, as evidenced by the steadily increasing number of newly approved fluorine-containing drugs. Herein, we identified in the ChEMBL database and analysed 1554 target-based FSAR sets (non-fluorinated compounds and their fluorinated analogues) comprising 966 unique non-fluorinated and 2457 unique fluorinated compounds active against 33 different aminergic GPCRs. Although a relatively small number of activity cliffs (defined as a pair of structurally similar compounds showing significant differences of activity −ΔpPot > 1.7) was found in FSAR sets, it is clear that appropriately introduced fluorine can increase ligand potency more than 50-fold. The analysis of matched molecular pairs (MMPs) networks indicated that the fluorination of the aromatic ring showed no clear trend towards a positive or negative effect on affinity; however, a favourable site for a positive potency effect of fluorination was the ortho position. Fluorination of aliphatic fragments more often led to a decrease in biological activity. The results may constitute the rules of thumb for fluorination of aminergic receptor ligands and provide insights into the role of fluorine substitutions in medicinal chemistry.Wojciech PietruśRafał KurczabDagmar StumpfeAndrzej J. BojarskiJürgen BajorathMDPI AGarticleG protein-coupled receptorsGPCRaminergic receptorsfluorineactivity cliffsMMPMicrobiologyQR1-502ENBiomolecules, Vol 11, Iss 1647, p 1647 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	G protein-coupled receptors GPCR aminergic receptors fluorine activity cliffs MMP Microbiology QR1-502
spellingShingle	G protein-coupled receptors GPCR aminergic receptors fluorine activity cliffs MMP Microbiology QR1-502 Wojciech Pietruś Rafał Kurczab Dagmar Stumpfe Andrzej J. Bojarski Jürgen Bajorath Data-Driven Analysis of Fluorination of Ligands of Aminergic G Protein Coupled Receptors
description	Currently, G protein-coupled receptors are the targets with the highest number of drugs in many therapeutic areas. Fluorination has become a common strategy in designing highly active biological compounds, as evidenced by the steadily increasing number of newly approved fluorine-containing drugs. Herein, we identified in the ChEMBL database and analysed 1554 target-based FSAR sets (non-fluorinated compounds and their fluorinated analogues) comprising 966 unique non-fluorinated and 2457 unique fluorinated compounds active against 33 different aminergic GPCRs. Although a relatively small number of activity cliffs (defined as a pair of structurally similar compounds showing significant differences of activity −ΔpPot > 1.7) was found in FSAR sets, it is clear that appropriately introduced fluorine can increase ligand potency more than 50-fold. The analysis of matched molecular pairs (MMPs) networks indicated that the fluorination of the aromatic ring showed no clear trend towards a positive or negative effect on affinity; however, a favourable site for a positive potency effect of fluorination was the ortho position. Fluorination of aliphatic fragments more often led to a decrease in biological activity. The results may constitute the rules of thumb for fluorination of aminergic receptor ligands and provide insights into the role of fluorine substitutions in medicinal chemistry.
format	article
author	Wojciech Pietruś Rafał Kurczab Dagmar Stumpfe Andrzej J. Bojarski Jürgen Bajorath
author_facet	Wojciech Pietruś Rafał Kurczab Dagmar Stumpfe Andrzej J. Bojarski Jürgen Bajorath
author_sort	Wojciech Pietruś
title	Data-Driven Analysis of Fluorination of Ligands of Aminergic G Protein Coupled Receptors
title_short	Data-Driven Analysis of Fluorination of Ligands of Aminergic G Protein Coupled Receptors
title_full	Data-Driven Analysis of Fluorination of Ligands of Aminergic G Protein Coupled Receptors
title_fullStr	Data-Driven Analysis of Fluorination of Ligands of Aminergic G Protein Coupled Receptors
title_full_unstemmed	Data-Driven Analysis of Fluorination of Ligands of Aminergic G Protein Coupled Receptors
title_sort	data-driven analysis of fluorination of ligands of aminergic g protein coupled receptors
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/cd62e2b920104ecb91d770b5e194e417
work_keys_str_mv	AT wojciechpietrus datadrivenanalysisoffluorinationofligandsofaminergicgproteincoupledreceptors AT rafałkurczab datadrivenanalysisoffluorinationofligandsofaminergicgproteincoupledreceptors AT dagmarstumpfe datadrivenanalysisoffluorinationofligandsofaminergicgproteincoupledreceptors AT andrzejjbojarski datadrivenanalysisoffluorinationofligandsofaminergicgproteincoupledreceptors AT jurgenbajorath datadrivenanalysisoffluorinationofligandsofaminergicgproteincoupledreceptors
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Data-Driven Analysis of Fluorination of Ligands of Aminergic G Protein Coupled Receptors

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