Potential Stereoselective Binding of Trans -(±)-Kusunokinin and Cis -(±)-Kusunokinin Isomers to CSF1R.

Breast cancer cell proliferation and migration are inhibited by naturally extracted trans -(-)-kusunokinin. However, three additional enantiomers of kusunokinin have yet to be investigated: trans -(+)-kusunokinin, cis -(-)-isomer and cis -(+)-isomer. According to the results of molecular docking studies of kusunokinin isomers on 60 breast cancer-related proteins, trans -(-)-kusunokinin was the most preferable and active component of the trans -racemic mixture. Trans -(-)-kusunokinin targeted proteins involved in cell growth and proliferation, whereas the cis -(+)-isomer targeted proteins involved in metastasis. Trans -(-)-kusunokinin targeted CSF1R specifically, whereas trans -(+)-kusunokinin and both cis -isomers may have bound AKR1B1. Interestingly, the compound's stereoisomeric effect may influence protein selectivity. CSF1R preferred trans -(-)-kusunokinin over trans -(+)-kusunokinin because the binding pocket required a ligand planar arrangement to form a π-π interaction with a selective Trp550. Because of its large binding pocket, EGFR exhibited no stereoselectivity. MD simulation revealed that trans -(-)-kusunokinin, trans -(+)-kusunokinin and pexidartinib bound CSF1R differently. Pexidartinib had the highest binding affinity, followed by trans -(-)-kusunokinin and trans -(+)-kusunokinin, respectively. The trans -(-)-kusunokinin-CSF1R complex was found to be stable, whereas trans -(+)-kusunokinin was not. Trans -(±)-kusunokinin, a potential racemic compound, could be developed as a selective CSF1R inhibitor when combined.