Identifying novel triazole-containing histone deacetylase 1 antitumor inhibitors through molecular simulations and ADME/T profiling

Histone deacetylase 1 (HDAC1), a pivotal epigenetic modulator, is critically involved in oncogenesis and serves as a promising target for anticancer drug discovery. In this study, 59 reported HDAC1 inhibitors were utilized to establish robust three-dimensional quantitative structure-activity relationship models for designing novel triazole-containing derivatives with optimized bioactivity and pharmacokinetic profiles. Comparative molecular field analysis ( n = 9, R2 = 0.966, q2 = 0.781) and comparative molecular similarity index analysis ( n = 6, R2 = 0.945; q2 = 0.778) confirmed the predictive reliability of these models. On the basis of the contour maps analysis, the key structural modification sites were determined, and seven promising analogs were reasonably designed. These candidates showed good drug-likeness in ADME/T profiling and formed stable complexes with HDAC1 in molecular simulations, underscoring their promising inhibitory potential. Our study provided a strategic framework for the discovery of HDAC1 drugs and identified promising leads for cancer therapeutics.