In silico design of HDAC6 inhibitors with neuroprotective effects

• Published in: Journal of biomolecular structure & dynamics 2022-01, Vol.40 (24), p.14204-14222
• Main Authors: Sixto-López, Yudibeth, Gómez-Vidal, José Antonio, de Pedro, Nuria, Bello, Martiniano, Rosales-Hernández, Martha Cecilia, Correa-Basurto, José
• Format: Article
• Language: English
• Subjects: docking; HDAC6; HDACi; Histone deacetylase; Histone Deacetylase 6 - chemistry; Histone Deacetylase Inhibitors - chemistry; Histone Deacetylase Inhibitors - pharmacology; Hydroxamic Acids - chemistry; Hydroxamic Acids - pharmacology; MD simulation; Molecular Docking Simulation; Molecular Dynamics Simulation; neuroprotection; Neuroprotective Agents - pharmacology
• ISSN: 0739-1102; 1538-0254
• DOI: 10.1080/07391102.2021.2001378

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