Journal
MOLECULES
Volume 28, Issue 2, Pages -Publisher
MDPI
DOI: 10.3390/molecules28020490
Keywords
G protein-coupled receptor; GPCR; fluorine; activity cliffs; AC; MMP; ChEMBL; induced fit docking; MD; QPLD
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In this study, a total of 898 F-containing isomeric analog sets were identified and analyzed for structure-activity relationship (SAR) in the ChEMBL database. The results showed significant differences in affinity for some isomeric compounds against different aminergic GPCRs, and the change of fluorine position could lead to a significant change in potency. Additionally, a computational workflow was proposed to score the fluorine positions in the molecule.
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-F(i)SAR sets active against 33 different aminergic GPCRs comprising a total of 2163 fluorinated (1201 unique) compounds. We found 30 F(i)SAR 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.
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