title: Discovery of DNA dyes Hoechst 34580 and 33342 as good candidates for inhibiting amyloid beta formation: in silico and in vitro study.
abstract: Combining Lipinski's rule with the docking and steered molecular dynamics simulations and using the PubChem data base of about 1.4 million compounds, we have obtained DNA dyes Hoechst 34580 and Hoechst 33342 as top-leads for the Alzheimer's disease. The binding properties of these ligands to amyloid beta (Aβ) fibril were thoroughly studied by in silico and in vitro experiments. Hoechst 34580 and Hoechst 33342 prefer to locate near hydrophobic regions with binding affinity mainly governed by the van der Waals interaction. By the Thioflavin T assay, it was found that the inhibition constant IC50 ≈ 0.86 and 0.68 μM for Hoechst 34580 and Hoechst 33342, respectively. This result qualitatively agrees with the binding free energy estimated using the molecular mechanic-Poisson Boltzmann surface area method and all-atom simulations with the AMBER-f99SB-ILDN force field and water model TIP3P. In addition, DNA dyes have the high capability to cross the blood brain barrier. Thus, both in silico and in vitro experiments have shown that Hoechst 34580 and 33342 are good candidates for treating the Alzheimer's disease by inhibiting Aβ formation.
authors: Institute for Computational Science and Technology, SBI Building, Quang Trung Software City, Tan Chanh Hiep Ward, District 12, Ho Chi Minh City, Vietnam.|Biomedical Engineering Department, University of Technology -VNU HCM, 268 Ly Thuong Kiet Str., Distr. 10, Ho Chi Minh City, Vietnam.|Division of Theoretical Physics, Dong Thap University, 783 Pham Huu Lau Street, Ward 6, Cao Lanh City, Dong Thap, Vietnam.
authors: Nguyen Quoc
authors: NQ
authors: Thai
authors: Genomics Research Center, Academia Sinica, Academia Rd., Sec. 2, Nankang Dist., Taipei 115, Taiwan.
authors: Ning-Hsuan
authors: NH
authors: Tseng
authors: Institute for Computational Science and Technology, SBI Building, Quang Trung Software City, Tan Chanh Hiep Ward, District 12, Ho Chi Minh City, Vietnam.
authors: Mui Thi
authors: MT
authors: Vu
authors: Institute for Computational Science and Technology, SBI Building, Quang Trung Software City, Tan Chanh Hiep Ward, District 12, Ho Chi Minh City, Vietnam.
authors: Tin Trung
authors: TT
authors: Nguyen
authors: Biomedical Engineering Department, University of Technology -VNU HCM, 268 Ly Thuong Kiet Str., Distr. 10, Ho Chi Minh City, Vietnam.
authors: Huynh Quang
authors: HQ
authors: Linh
authors: Institute of Physics, Academia Sinica, 128 Academia Road Section 2, Taipei, 11529, Taiwan.|National Center for Theoretical Sciences, National Tsing Hua University, 101 Kuang-Fu Road Section 2, Hsinch, 30013, Taiwan.|Business School, University of Shanghai for Science and Technology, 334 Jun Gong Road, Shanghai, 200093, China.
authors: Chin-Kun
authors: CK
authors: Hu
authors: Genomics Research Center, Academia Sinica, Academia Rd., Sec. 2, Nankang Dist., Taipei 115, Taiwan.
authors: Yun-Ru
authors: YR
authors: Chen
authors: Institute for Computational Science and Technology, SBI Building, Quang Trung Software City, Tan Chanh Hiep Ward, District 12, Ho Chi Minh City, Vietnam. masli@ifpan.edu.pl.|Institute of Physics, Polish Academy of Sciences, Al. Lotnikow 32/46, 02-668, Warsaw, Poland. masli@ifpan.edu.pl.
authors: Mai Suan
authors: MS
authors: Li
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D001562:Benzimidazoles / Q000494:pharmacology*; D004396:Coloring Agents / Q000494:pharmacology*; D055808:Drug Discovery; D006801:Humans; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D066329:Protein Aggregates / Q000187:drug effects*
chemical_list: D016229:Amyloid beta-Peptides; D001562:Benzimidazoles; D004396:Coloring Agents; C572112:Hoechst 34580; D066329:Protein Aggregates; C017807:bisbenzimide ethoxide trihydrochloride
keywords: Alzheimer’s disease; Amyloid beta fibril; DNA dyes; Drug design; Hoechst 33342; Hoechst 34580