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

Abstract

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.

Trans-(±)-Kusunokinin Binding to AKR1B1 Inhibits Oxidative Stress and Proteins Involved in Migration in Aggressive Breast Cancer

“…We reported that ( )KU suppressed MCF7 cell proliferation through its binding with CSF1R. Moreover, using a computational simulation, we also found that ( )KU bound MMP-12, HSP90-α, CyclinB1 and MEK1 [ 12 , 13 ]. Another reason for the effect of ( )KU on MCF7 is the characterization of the cells.…”

“…In addition, trans -( )-kusunokinin (( )KU) inhibits tumor growth and migration with no side effects in NMU-induced mammary tumor rats [ 11 ]. ( )KU mainly binds to colony-stimulating factor 1 receptor (CSF1R) to suppress breast cancer proliferation [ 12 ], while some trans -( )-kusunokinin and trans -( )-isoforms could inhibit intracellular proteins, such as heat-shock protein 90 alpha (Hsp90-α) and aldo-keto reductase family 1 member B1 (AKR1B1) [ 13 ]. Interestingly, AKR1B1 was predicted to be a potential ( )KU target with a similarly stabilized orientation in the active binding pocket to CSF1R using π–π interactions.…”

Novel Lawsone–Quinoxaline Hybrids as New Dual Binding Site Acetylcholinesterase Inhibitors

“…The MD simulation began with the best docked pose from the molecular docking study, like previous studies. , Under the periodic boundary condition, the steepest descent method for 1000 steps and the conjugate gradient method for 1000 steps were used. To deal with nonbonded/electrostatic interaction, the NVT simulation was set at 298 K (25 °C) with a cutoff of 16 Å. Harmonic restraint was applied to the compound–protein coordinates with force constants of 200, 100, 50, 25, and 10 kcal mol –1 Å –2 .…”

Colony-stimulating factor 1 receptor: a novel target for cancer immunotherapy

“…The topological discrepancy may translate into several distinct yet overlapping downstream effects. Conclusively, the binding of either ligand induces CSF1R dimerization and releases of the intracellular tyrosine kinase from an autoinhibitory state [4,5]. Kinase activation further triggers the recruitment of several downstream effector proteins, including PI3K, JAK, and MAPKs, whose activations are essential for cell survival, proliferation, and differentiation [6].…”