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

Biomolecules

Jürgen Bajorath¹  Dagmar Stumpfe¹  Andrzej J. Bojarski²  Rafał Kurczab²  Wojciech Pietruś² 

[1] Department of Life Science Informatics, LIMES Program Unit Chemical Biology and Medicinal Chemistry, B-IT, Rheinische Friedrich-Wilhelms-Universität, Friedrich-Hirzebruch-Allee 6, D-53115 Bonn, Germany;Department of Medicinal Chemistry, Maj Institute of Pharmacology, Polish Academy of Sciences, Smetna 12, 31-343 Krakow, Poland;

关键词: G protein-coupled receptors;    GPCR;    aminergic receptors;    fluorine;    activity cliffs;    MMP;   

DOI  :  10.3390/biom11111647

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown