Nowadays, significant progress has been made in the development of selective histone deacetylase 6 (HDAC6) inhibitors, exerting great potential in the treatment of various malignant tumors and neurodegenerative diseases. Previously, selective inhibitory activities of HDAC inhibitors were generally considered sensitive to the interactions between the Cap group and the binding site of HDAC6, and a large number of selective HDAC6 inhibitors have been designed and synthesized based on the strategy. However, some inhibitors without Cap group could also exhibit excellent potency and selective inhibition towards HDAC6, and in this study, BRD9757 and compound 8, as capless selective HDAC6 inhibitors, were selected as molecular probes to explore the difference of their binding interactions in HDAC1&6. Through the analysis of binding‐free energies and conformational rearrangements after 1 μs molecular dynamics simulation, it could be learned that although the residues in the binding site remained highly consistent, the binding mechanisms of BRD9757 and compound 8 in HDAC1&6 were different, which will provide valuable hints for the discovery of novel selective HDAC6 inhibitors.

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