Abstract
Currently, G protein-coupled receptors (GPCRs) constitute a significant group of membrane-bound receptors representing more than 30% of therapeutic targets. Fluorine is commonly used in designing highly active biological compounds, as evidenced by the steadily increasing number of drugs by the Food and Drug Administration (FDA). Herein, we identified and analyzed 898 target-based F-containing isomeric analog sets for SAR analysis in the ChEMBL database—FiSAR sets active against 33 different aminergic GPCRs comprising a total of 2163 fluorinated (1201 unique) compounds. We found 30 FiSAR sets contain activity cliffs (ACs), defined as pairs of structurally similar compounds showing significant differences in affinity (≥50-fold change), where the change of fluorine position may lead up to a 1300-fold change in potency. The analysis of matched molecular pair (MMP) networks indicated that the fluorination of aromatic rings showed no clear trend toward a positive or negative effect on affinity. Additionally, we propose an in silico workflow (including induced-fit docking, molecular dynamics, quantum polarized ligand docking, and binding free energy calculations based on the Generalized-Born Surface-Area (GBSA) model) to score the fluorine positions in the molecule.
Funder
National Science Centre, Poland
Subject
Chemistry (miscellaneous),Analytical Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Molecular Medicine,Drug Discovery,Pharmaceutical Science
Reference44 articles.
1. Evolutionary association of receptor-wide amino acids with G protein–coupling selectivity in aminergic GPCRs;Erol;Life Sci. Alliance,2022
2. Structural and Functional Diversity of Animal Toxins Interacting With GPCRs;Robin;Front. Mol. Biosci.,2022
3. Agarwal, P., Huckle, J., Newman, J., and Reid, D.L. (2022). Trends in small molecule drug properties: A developability molecule assessment perspective. Drug Discov. Today, 103366.
4. Pietruś, W., Kurczab, R., Stumpfe, D., Bojarski, A.J., and Bajorath, J. (2021). Data-driven analysis of fluorination of ligands of aminergic g protein coupled receptors. Biomolecules, 11.
5. Fluorine-Containing Drugs Approved by the FDA in 2018;Mei;Chem.–A Eur. J.,2019
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