Histone deacetylase 8 in focus: Decoding structural prerequisites for Histone deacetylase 8 in focus: Decoding structural prerequisites for innovative epigenetic intervention beyond hydroxamates innovative epigenetic intervention beyond hydroxamates

Histone deacetylase 8 (HDAC8) inhibitors play a pivotal role in epigenetic regulation. Numerous HDAC8 inHistone deacetylase 8 (HDAC8) inhibitors play a pivotal role in epigenetic regulation. Numerous HDAC8 inhibitors (HDAC8is), that are non-hydroxamates have been identified to date, and a few of them exhibit antihibitors (HDAC8is), that are non-hydroxamates have been identified to date, and a few of them exhibit antiproliferative activity that is on par with hydroxamates. While many non-hydroxamate-based HDAC8is have proliferative activity that is on par with hydroxamates. While many non-hydroxamate-based HDAC8is have demonstrated selectivity, hydroxamate-based HDAC8is, like Vorinostat and TSA, have a tendency of nondemonstrated selectivity, hydroxamate-based HDAC8is, like Vorinostat and TSA, have a tendency of nonspecificity among the different HDAC isoforms. Moreover, because of the unfavorable toxic side effects, there specificity among the different HDAC isoforms. Moreover, because of the unfavorable toxic side effects, there are significant concerns surrounding the use of hydroxamate derivatives as therapeutic agents in cancer as well are significant concerns surrounding the use of hydroxamate derivatives as therapeutic agents in cancer as well as other chronic diseases. Consequently, the research on non-hydroxamate-based HDAC8is is of utmost priority. as other chronic diseases. Consequently, the research on non-hydroxamate-based HDAC8is is of utmost priority. In the present study, a comprehensive study was presented to unravel the structural requirements of nonIn the present study, a comprehensive study was presented to unravel the structural requirements of nonhydroxamate-based HDAC8is from a diverse set of 866 compounds. The study utilized Classification-based hydroxamate-based HDAC8is from a diverse set of 866 compounds. The study utilized Classification-based Quantitative Structure-Activity Relationship (QSAR) analysis, incorporating Bayesian classification, Recursive Quantitative Structure-Activity Relationship (QSAR) analysis, incorporating Bayesian classification, Recursive partitioning, and other machine learning methods to pinpoint the key structural features essential for HDAC8 partitioning, and other machine learning methods to pinpoint the key structural features essential for HDAC8 inhibition. To underscore and gain deeper insights into the identified structural features, molecular docking, and inhibition. To underscore and gain deeper insights into the identified structural features, molecular docking, and molecular dynamic (MD) simulation studies were conducted. The integration of these computational approaches molecular dynamic (MD) simulation studies were conducted. The integration of these computational approaches unveiled key structural motifs essential for potent HDAC8 inhibitory activity, shedding light on the molecular unveiled key structural motifs essential for potent HDAC8 inhibitory activity, shedding light on the molecular basis of HDAC8 inhibition using non-hydroxamates. basis of HDAC8 inhibition using non-hydroxamates.