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.
journal_name
J Comput Aided Mol Desjournal_title
Journal of computer-aided molecular designauthors
Thai NQ,Tseng NH,Vu MT,Nguyen TT,Linh HQ,Hu CK,Chen YR,Li MSdoi
10.1007/s10822-016-9932-1subject
Has Abstractpub_date
2016-08-01 00:00:00pages
639-50issue
8eissn
0920-654Xissn
1573-4951pii
10.1007/s10822-016-9932-1journal_volume
30pub_type
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