In silico design of HDAC6 inhibitors with neuroprotective effects

Abstract

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

Keywords:

• Histone deacetylase
• docking
• MD simulation
• neuroprotection
• HDAC6
• HDACi

Declaration of competing interests

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Disclosure statement

No potential conflict of interest was reported by the authors. 

Author contributions

YSL, performed the computational studies, chemical synthesis and wrote the paper; JAGV, did chemical synthesis and wrote the paper; MCRH and NP, performed neuroprotection assays and wrote the paper; MB, did molecular dynamics simulation and docking; JBC, designed the project, wrote the paper and did computational studies.

Additional information

Funding

We gratefully acknowledge to CONACYT (Grants: CB-254600 SEP-CONACYT-ANUIES-ECOS Francia: 296636 and 317214), to Instituto Politécnico Nacional (Grant: Proyectos Insignia IPN-2015), and to COFAA-SIP/IPN. YSL thanks to CONACYT by Ph.D. scholarship and SECTEI (Secretaria de Educación, Ciencia, Tecnología e Innovación de la Ciudad de México) for Postdoctoral Fellowship. We would like to express our very great appreciation to Dr. Bruno Landeros-Rivera for his valuable and constructive suggestions to improve the manuscript.