Computational investigation of possible inhibitors of the winged-helix domain of MUS81

Abstract

The methyl methanesulfonate and ultraviolet sensitive 81 (MUS81) is a structure-specific endonuclease that is highly conserved in eukaryotes and essential for homologous recombination repair. The winged-helix domain at the N-terminus of MUS81 (wMUS81) can bind DNA substrates and regulate the endonuclease activity. The repression of MUS81 activity could enhance the sensitivity to antitumor compounds of different tumour cells. Thus, MUS81 is a potential therapeutic target in cancer therapy. However, specific inhibitors of MUS81 have remained elusive. Here, for the first time, we attempt to discover the compounds disrupting the wMUS81 activity. The binding affinity of available drugs to wMUS81 was first estimated by molecular docking. pK_a values were taken into consideration to eliminate unlikely protonation states of the ligands. Top-lead compounds were then estimated the binding affinity using the fast pulling ligand simulations. Finally, the free energy perturbation method accurately defined the absolute binding free energy of the top four ligands, revealing the most potential inhibitors of wMUS81 including simeprevir and nilotinib. Binding of simeprevir destabilizes the β-hairpin region of wMUS81, likely disturbing the wMUS81 function. The van der Waals free binding energy majorly modulates the ligand-binding mechanism. The two conserved residues Leu189 and Arg196 are likely important in monitoring the interacting process of simeprevir to wMUS81.

Keywords: Binding free energy; FEP; FPL; Molecular docking; Nilotinib; Simeprevir; pK(a) calculation; wMUS81.