In silico design of HDAC6 inhibitors with neuroprotective effects
| Autor: | Yudibeth Sixto-Lopez, José Correa-Basurto, Martiniano Bello, José A. Gómez-Vidal, Martha Cecilia Rosales-Hernández, Nuria de Pedro |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Hydroxamic acid
Stereochemistry In silico General Medicine Molecular Dynamics Simulation Histone Deacetylase 6 Hydroxamic Acids Neuroprotection In vitro Molecular Docking Simulation Histone Deacetylase Inhibitors chemistry.chemical_compound Neuroprotective Agents chemistry Structural Biology Docking (molecular) Enantiomer Molecular Biology Lead compound Mitochondrial transport |
| Zdroj: | Journal of biomolecular structuredynamics. 40(24) |
| ISSN: | 1538-0254 |
| Popis: | HDAC6 has emerged as a molecular target to treat neurodegenerative disorders, due to its participation in protein aggregate degradation, oxidative stress process, mitochondrial transport, and axonal transport. Thus, in this work we have designed a set of 485 compounds with hydroxamic and bulky-hydrophobic moieties that may function as HDAC6 inhibitors with a neuroprotective effect. These compounds were filtered by their predicted ADMET properties and their affinity to HDAC6 demonstrated by molecular docking and molecular dynamics simulations. The combination of in silico with in vitro neuroprotective results allowed the identification of a lead compound (FH-27) which shows neuroprotective effect that could be due to HDAC6 inhibition. Further, FH-27 chemical moiety was used to design a second series of compounds improving the neuroprotective effect from 2- to 10-fold higher (YSL-99, YSL-109, YSL-112, YSL-116 and YSL-121; 1.25 ± 0.67, 1.82 ± 1.06, 7.52 ± 1.78, 5.59 and 5.62 ± 0.31 µM, respectively). In addition, the R enantiomer of FH-27 (YSL-106) was synthesized, showing a better neuroprotective effect (1.27 ± 0.60 µM). In conclusion, we accomplish the in silico design, synthesis, and biological evaluation of hydroxamic acid derivatives with neuroprotective effect as suggested by an in vitro model.Communicated by Ramaswamy H. Sarma. |
| Databáze: | OpenAIRE |
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