Structural dynamics of the cooperative binding of small inhibitors in human cytochrome P450 2C9.

Some non-steroidal anti-inflammatory drugs (NSAIDs) exhibit atypical kinetic behavior when binding together with dapsone in CYP2C9. However, few studies about the detailed multi-drug binding dynamics in CYP2C9 have been reported. Here, molecular docking and molecular dynamics (MD) simulations are performed to explore the cooperative binding of dapsone and three NSAIDs in CYP2C9. The docking results show that dapsone bind to not only the distal primay bind site but also the active site above the heme group. Flurbiprofen/naproxen and piroxicam are located in the active site and the primary binding site of CYP2C9, respectively. It is noted that some key hydrogen bond (H-bond) and hydrophobic interactions mediate the conformational changes of substrates. Moreover, the calculated binding affinity is in line with experimental results. Further, the residue energy decomposition reveals that van der Waals energies of backbone/side-chain atoms dominate the substrate-binding and they can be ascribed to π···π, C-H···π, C-H⋯H-C interactions.