Abstract
The winged-helix domain of the methyl methanesulfonate and ultraviolet-sensitive 81 (wMUS81) is a potential cancer drug target. In this context, marine fungi compounds were indicated to be able to prevent wMUS81 structure via atomistic simulations. Eight compounds such as D197 (Tryptoquivaline U), D220 (Epiremisporine B), D67 (Aspergiolide A), D153 (Preussomerin G), D547 (12,13-dihydroxyfumitremorgin C), D152 (Preussomerin K), D20 (Marinopyrrole B) and D559 (Fumuquinazoline K) were indicated that they are able to prevent the conformation of wMUS81 via forming a strong binding affinity to the enzyme via perturbation approach. The electrostatic interaction is the dominant factor in the binding process of ligands to wMUS81. The residues Trp55, Arg59, Leu62, His63 and Arg69 were found to frequently form non-bonded contacts and hydrogen bonds to inhibitors. Moreover, the influence of the ligand D197, which formed the lowest binding free energy to wMUS81, on the structural change of enzyme was investigated using replica exchange molecular dynamics simulations. The obtained results indicated that D197, which forms a strong binding affinity, can modify the structure of wMUS81. Overall, the marine compounds probably inhibit wMUS81 due to forming a strong binding affinity to the enzyme as well as altering the enzymic conformation.
Highlights
Methyl methanesulfonate ultraviolet-sensitive gene clone 1 (MUS81) is a member of the Xpf family of structure-specific DNA endonucleases, which play overlapping and essential roles in the completion of royalsocietypublishing.org/journal/rsos R
The winged-helix domain at the N-terminus of MUS81 mutations was indicated to reduce the binding of the DNA substrates and modulate the endonuclease activity of the MUS81 complex [3] leading to a crucial role of MUS81 in DNA replication, repair and transcription [4]
The binding poses between winged-helix domain at the N-terminus of MUS81 (wMUS81) and the 16 topleads inhibitors were used as initial conformations of atomistic molecular dynamics (MD) simulations
Summary
Methyl methanesulfonate ultraviolet-sensitive gene clone 1 (MUS81) is a member of the Xpf family of structure-specific DNA endonucleases, which play overlapping and essential roles in the completion of royalsocietypublishing.org/journal/rsos R. Inhibitions of MUS81 improve the chemical sensitivity of various anti-cancer drugs, such as 5-fluorouracil, camptothecin, olaparib and cisplatin by different mechanisms in diverse cancer cells. The downregulation of MUS81 enhanced the sensitivity to camptothecin and olaparib in serous ovarian cancer cell lines and xenograft model [5,6], and played a role as a potential marker for the malignancy of gastric cancer [7]. The inhibition of MUS81 by siRNA reinforced the sensitiveness to 5-fluorouracil in breast carcinoma cell lines [8]. MUS81 inhibition enhanced the sensitivity to anti-tumour in epithelial ovarian cancer via regulating CyclinB pathway as well [4]. MUS81 inhibitors that bind to MUS81 might enhance the chemosensitivity in the cancer cells leading to improving the efficiency of therapeutic treatment
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