Revealing inhibition difference between PFI-2 enantiomers against SETD7 by molecular dynamics simulations, binding free energy calculations and unbinding pathway analysis

SETD7 is associated with multiple diseases related signaling pathways. (R)-PFI-2 is the first SETD7 inhibitor with nanomolar inhibitory potency. The activity of (R)-PFI-2 is about 500 times over that of (S)-PFI-2. Understanding the mechanism behind this difference will be helpful to discovery and design of more potent SETD7 inhibitors. A computational study combining molecular dynamics simulation, binding free energy calculations, and residue interaction network (RIN) was performed on the (S)-PFI-2/SETD7 and (R)-PFI-2/SETD7 complexes to explore the molecular mechanism behind the different inhibition activity. The results from Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) calculation show (R)-PFI-2 has lower binding free energy. Residues H252, D256, L267, Y335, G336 and H339 are responsible for the binding of SETD7 to the (R)-PFI-2. RIN analysis indicates van der Waals interaction is critical for the binding of (R)-PFI-2. The results from adaptive basing force (ABF) simulation confirm that the free energy barrier of (R)-PFI-2 dissociating from the SETD7 is larger than that of (S)-PFI-2. (S)-PFI-2 and (R)-PFI-2 dissociate from the SETD7 binding site along different reaction coordinate and have potential mean of force (PMF) depth. Our simulations results will be useful to understand molecular mechanism of activity difference between PFI-2 enantiomers against SETD7.