Stereoisomeric effects of kusunokinin isomers on CSF1R selectivity

Background: Naturally extracted trans-(−)-kusunokinin from P. nigrum showed anticancer activities via binding and inhibition of CSF1R. However, the synthetic racemic mixtures trans-(−)- trans-(+)-kusunokinin (trans-(±)-kusunokinin) exhibited different effects on breast cancer cell lines. It was hypothesized that trans-(±)-kusunokinin bind to additional molecules, including AKR1B1. Previously, we found trans-(−)-isomer had better relative energies (ΔGbind) than trans-(+)-isomer in every studied proteins. Chiral carbon configurations kusunokinin may also result cis-(−)-isomer cis-(+)-isomer. Differences stereochemistry lead stereoisomeric preference for target protein selection mode variety among four isomers. Material Methods: The enantiomers: trans-(−), trans-(+), cis-(−) cis-(+)-isomer investigated 57 proteins related CSF1R-breast progression pathway, grouped by their main functions. potential determined isomers’ ΔGbind sites, compared known inhibitors. A preferable form isomers proposed using molecular docking combined with our ranking scoring procedure. Contributing factors pocket’s stereoselectivity were observed. Aggregation cis-(±)-kusunokinin evaluated Molecular dynamics simulation (MD). Results: Trans-(−)-kusunokinin selectively targeted CSF1R whereas cis-(-) inhibited AKR1B1 without stereoselectivity. most preferred isoform while potentially metastasis shared a nature large spherical pockets, as well lack aromatic residues within sites. narrow pocket required planar arrangement ligand π-π interaction Trp550, selective residue juxtamembrane domain region. MD highlighted stability trans-(+)-kusunokinin. two racemate pairs not affected binding. Conclusions: Trans-(±)-kusunokinin mainly trans-(−)-isoform CSF1R, molecules trans-(+)-isoform, AKR1B1, CDK2, COX2, EGFR, Hsp90a, JAK3 MNK2. did selectivity. Therefore, promising inhibitor cis-(±)-isomer be further investigated. No conflict interest.