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A class I histone deacetylase HDAC8 is associated with several diseases, including cancer, intellectual impairment and parasite infection. Most of the HDAC inhibitors that have so far been found to inhibit HDAC8 limit their efficacy in the clinic by producing toxicities. It is therefore very desirable to develop specific HDAC8 inhibitors. The emergence of HDAC inhibitors derived from natural sources has become quite popular. In recent decades, it has been shown that naturally occurring HDAC inhibitors have strong anticancer properties. A total of 0.2 million natural compounds were screened against HDAC8 from the Universal Natural Product Database (UNPD). Molecular docking was performed for these natural compounds and the top six hits were obtained. In addition, molecular dynamics (MD) simulations were used to evaluate the structural stability and binding affinity of the inhibitors, which showed that the protein–ligand complexes remained stable throughout the 100 ns simulation. MM-PBSA method demonstrated that the selected compounds have high affinity towards HDAC8. We infer from our findings that Hit-1 (−29.35 kcal mol −1 ), Hit-2 (−29.15 kcal mol −1 ) and Hit-6 (−30.28 kcal mol −1 ) have better binding affinity and adhesion to ADMET (absorption, distribution, metabolism, excretion and toxicity) characteristics against HDAC8. To compare our discussions and result in an effective way. We performed molecular docking, MD and MM-PBSA analysis for the FDA-approved drug romidepsin. The above results show that our hits show better binding affinity than the compound romidepsin (−12.03 ± 4.66 kcal mol −1 ). The important hotspot residues Asp29, Ile34, Trp141, Phe152, Asp267, Met274 and Tyr306 have significantly contributed to the protein–ligand interaction. These findings suggest that in vitro testing and additional optimization may lead to the development of HDAC8 inhibitors. Communicated by Ramaswamy H. Sarma

Discovery of novel HDAC8 inhibitors from natural compounds by in silico high throughput screening