Binding patterns of derivatives of fisetin and chrysin to the enzyme complex cyclin-dependent kinase 6/cyclin D

Clinical inhibitors of cell-cycle regulatory enzyme cyclin-dependent kinase 6 (CDK6) are not free of harmful consequences to human bodies. Flavonoids fisetin and chrysin bestow anti-cancer benefits by inhibiting the activities of CDK6 with strong binding affinities. To understand the structure requirement of such inhibitory behaviour, docking and molecular dynamics (MD) simulations were performed on chosen three derivatives each of fisetin and chrysin along with the parent flavonoids. Docking studies revealed more negative binding energies of the derivatives than the parent molecules. MD simulations suggested appreciable stability of the derivatives in the systems. CDK6 association with ring A OH was minute in fisetin, replacing the same with one alpha-naphtha group in fisetin_3 resulting in enhanced long-range interactions. Interaction of ring A OH groups was significant in chrysin. The additional fluorine atom along with ring C OH and OCH3substituents in chrysin_2 induced a greater number of favourable interactions with CDK6.The selected ligands were docked into the ATP competitive binding site of rigid receptor CDK6/cyclin D using AutoDock 4.2. Stable conformations of the ligands were searched using Lamarckian Genetic Algorithm. Lowest energy poses of the best docked derivatives that resembled experimental conformation of co-crystallised ligand fisetin (fisetin_3, chrysin_3 and chrysin_2), along with fisetin and chrysin which were subjected to MD simulations. Ligand protein interactions in an aqueous environment were modelled using CHARMM27 force field accommodated in GROMACS 2022. MM-PBSA binding free energies of the ligands to CDK6 were computed using g_mmpbsa module of GROMACS.