Virtual screening and molecular dynamics simulation studies to identify potential inhibitors of Furin

doi:10.7523/j.ucas.2021.0044

Abstract

Abstract: In this study, virtual screening based on Furin receptor was carried out by means of molecular docking and molecular dynamics simulations to find potential inhibitors of Furin. The pharmacophore model based on Furin receptor was constructed by Sybyl. Drug molecules were screened from ZINC database according to the pharmacophore model. The screened drug molecules were docked with Furin protein. Finally, four qualified drug molecules were screened. The four complexes were calculated by molecular dynamics simulations for 100ns. RMSD and RMSF were calculated. The binding energies of Furin receptors with drug molecular ligands were analyzed by MMGBSA. It was found that the binding energy of Furin-ZINC7664 was the lowest one, which indicated that the drug molecule ZINC7664 is the most stable potential inhibitor to Furin and could be used to design the effective anti-Furin drugs.

Key words: Furin, virtual screening, molecular docking, molecular dynamics simulation

CLC Number:

O642

SUN Fenglei, LI Xiaoyi. Virtual screening and molecular dynamics simulation studies to identify potential inhibitors of Furin[J]. Journal of University of Chinese Academy of Sciences, 2023, 40(2): 173-178.

References

[1] Fuller R S, Brake A J, Thorner J. Intracellular targeting and structural conservation of a prohormone-processing endoprotease[J]. Science, 1989, 246(4929):482-486.
[2] Roebroek A J M, Schalken J A, Bussemakers M J G, et al. Characterization of human c-Fes/fps reveals a new transcription unit (fur) in the immediately upstream region of the proto-oncogene[J]. Molecular Biology Reports, 1986, 11(2):117-125.
[3] Nakayama K. Furin:a mammalian subtilisin/Kex2p-like endoprotease involved in processing of a wide variety of precursor proteins[J]. The Biochemical Journal, 1997, 327(Pt 3):625-635.
[4] Osadchuk T V, Shybyryn O V, Kibirev V K. Chemical structure and properties of low-molecular furin inhibitors[J]. Ukrainian Biochemical Journal, 2016, 88(6):5-25.
[5] Gawlik K, Shiryaev S A, Zhu W, et al. Autocatalytic activation of the furin zymogen requires removal of the emerging enzyme's N-terminus from the active site[J]. PLoS One, 2009, 4(4):e5031.
[6] Thomas G. Furin at the cutting edge:from protein traffic to embryogenesis and disease[J]. Nat Rev Mol Cell Biol, 2002, 3(10):753-766.
[7] Salvas A, Benjannet S, Reudelhuber T L, et al. Evidence for proprotein convertase activity in the endoplasmic reticulum/early Golgi[J]. FEBS Letters, 2005, 579(25):5621-5625.
[8] 张友义, 刘伟娜, 赵慧娜,等. Furin的生物学功能[J]. 生命的化学, 2019, 39(2):353-359.
[9] Henrich S, Cameron A, Bourenkov G P, et al. The crystal structure of the proprotein processing proteinase furin explains its stringent specificity[J]. Nature Structural Biology, 2003, 10(7):520-526.
[10] Rockwell N C, Thorner J W. The kindest cuts of all:crystal structures of Kex2 and furin reveal secrets of precursor processing[J]. Trends in Biochemical Sciences, 2004, 29(2):80-87.
[11] Jaaks P, Bernasconi M. The proprotein convertase furin in tumour progression[J]. International Journal of Cancer, 2017, 141(4):654-663.
[12] 王涛, 赵晶, 杨安钢. 弗林蛋白酶:一种广泛参与前体蛋白切割的内切蛋白酶[J]. 医学分子生物学杂志, 2006, 3(3):202-205.
[13] Li Y F, Chu J H, Li J, et al. Cancer/testis antigen-Plac1 promotes invasion and metastasis of breast cancer through Furin/NICD/PTEN signaling pathway[J]. Molecular Oncology, 2018, 12(8):1233-1248.
[14] Zhang Y, Zhou M, Wei H, et al. Furin promotes epithelial-mesenchymal transition in pancreatic cancer cells via Hippo-YAP pathway[J]. International Journal of Oncology, 2017, 50(4):1352-1362.
[15] Longuespée R, Couture F, Levesque C, et al. Implications of proprotein convertases in ovarian cancer cell proliferation and tumor progression:insights for PACE4 as a therapeutic target[J]. Translational Oncology, 2014, 7(3):410-419.
[16] Sergeeva O A, van der Goot F G. Anthrax toxin requires ZDHHC₅-mediated palmitoylation of its surface-processing host enzymes[J]. PNAS, 2019, 116(4):1279-1288.
[17] 韩锦铂. 前体蛋白加工酶furin的天然抑制剂及相互作用蛋白研究[D]. 上海:中国科学院研究生院(上海生命科学研究院),2007.
[18] Basak A, Lazure C. Synthetic peptides derived from the prosegments of proprotein convertase 1/3 and furin are potent inhibitors of both enzymes[J]. The Biochemical Journal, 2003, 373(Pt 1):231-239.
[19] Villemure M, Fournier A, Gauthier D, et al. Barley serine proteinase inhibitor 2-derived cyclic peptides as potent and selective inhibitors of convertases PC₁/3 and furin[J]. Biochemistry, 2003, 42(32):9659-9668.
[20] Jean F, Boudreault A, Basak A, et al. Fluorescent peptidyl substrates as an aid in studying the substrate specificity of human prohormone convertase PC₁ and human furin and designing a potent irreversible inhibitor[J]. Journal of Biological Chemistry, 1995, 270(33):19225-19231.
[21] Basak A, Cooper S, Roberge A G, et al. Inhibition of proprotein convertases-1, -7 and furin by diterpines of Andrographis paniculata and their succinoyl esters[J]. The Biochemical Journal, 1999, 338(Pt 1):107-113.
[22] Podsiadlo P, Komiyama T, Fuller R S, et al. Furin inhibition by compounds of copper and zinc[J]. Journal of Biological Chemistry, 2004, 279(35):36219-36227.
[23] Dahms S O, Arciniega M, Steinmetzer T, et al. Structure of the unliganded form of the proprotein convertase furin suggests activation by a substrate-induced mechanism[J]. Proceedings of the National Academy of Sciences of the United States of America, 2016, 113(40):11196-11201.
[24] 方磊, 计明娟. PTP1B选择性抑制剂的分子动力学模拟及结合自由能计算[J]. 中国科学院研究生院学报, 2009, 26(1):58-64.
[25] 侯廷军, 朱丽荔, 陈丽蓉,等. EGFR和4-苯胺喹唑啉类抑制剂之间相互作用模式的研究[J]. 化学学报, 2002, 60(6):1023-1028.