In silico screening of small molecule modulators and their binding studies against human sirtuin-6 protein

Abstract

Sirtuin-6 (SIRT6), class III family of deacetylase regulates several biological functions, including transcriptional repression, telomere maintenance, and DNA repair. It is unique among sirtuin family members with diverse enzymatic functions: mono-ADP-ribosylase, deacetylase and defatty-acylase. The studies so far implicated SIRT6 role in lifespan extension, tumor suppression, and is considered as an attractive drug target for aging-related disease. In this study, we have carried out in silico screening for human SIRT6 modulators using NCI Diversity Set III library, molecular dynamic (MD) simulations to analyze the protein-ligand interaction, and validated their binding-affinity ($K_d$) using MicroScale Thermophoresis. This study yielded two novel compounds, ((3Z)-3-((4-(dimethylamino)phenyl)methylidene)-5-(5,6,7,8-tetrahydronaphthalen-2-yl)furan-2-one and 5-phenyl-2-(5-phenyl-2,3-dihydro-1,3-benzoxazol-2-yl)-2,3-dihydro-1,3-benzoxazole showing high-affinity interaction for SIRT6. The structural analysis from MD simulation suggests both compounds might act as substrate-analogs or mimic the nicotinamide binding. On considering the uniqueness of SIRT6 substrate binding acyl channel among sirtuin family member, binding of both compounds to the above site suggesting their specificity for SIRT6 isoform. Therefore, it may form the basis for the development of potential modulators for human SIRT6.

Communicated by Ramaswamy H. Sarma

Keywords:

• Histone deacetylase
• molecular dynamics simulations
• NAD⁺
• Sirtuin-6

Acknowledgments

The authors thank Dr. S. Thiyagarajan, Institute of Bioinformatics and Applied Biotechnology (IBAB), Bengaluru for his scientific input in MMGBSA calculations. S.U is grateful to the Council of Scientific and Industrial Research (CSIR), Government of India, for SRF fellowship (09/490(0103)/2019).

Disclosure statement

No potential conflict of interest was reported by the authors.

Author contributions

S.J. carried out cloning and MST analysis. S.A., S.U. and V.H. carried out docking and MD simulation studies. H.G. supported in cloning. P.D. supported in biophysical studies. S.P. and B.P. conceived the project, designed the experiments, and supervision. S.A., B.P. and S.P. analyzed and wrote the original draft.

Additional information

Funding

This work is supported by NIMHANS Intramural research grant (NIMH/PROJ/PS/575) awarded to S.P. H.G is supported by the fellowship program DBT-JRF (DBT/2019/NIMHANS/1275) from the Department of Biotechnology, Ministry of Science and Technology, Government of India. B.P is grateful to the SERB-Department of Science and Technology (DST), Government of India (SR/SO/BB-0108/2012; DST-FIST: SR/FST/LSI/2017(C)), and to ICMR, Government of India (ISRM/12(04)/2019.