Development of Novel Hydroxy Amide‐Based HDAC1 Inhibitors: Integrated Pharmacophore Modelling, 3D‐QSAR, and Virtual Screening Studies

Abstract Histone deacetylases (HDAC) are well‐established epigenetic targets for cancer therapy, with several HDAC inhibitors already approved for clinical use. Despite their potential, the clinical application of HDAC inhibitors, particularly HDAC1‐selective compounds, faces significant challenges. These include poor pharmacokinetics, limited bioavailability, and a lack of selectivity, which often necessitates to combine these inhibitors with other drugs for improved efficacy. Their limitations as standalone therapies emphasize the urgent need for further research and development. In this study, the dataset of 71 compounds were used to generate various pharmacophore models, among them DDRRR_1 was generated as the best pharmacophore model with a survival score of 6.148. The 3D‐QSAR data of theses compound showed a significant result with the values of R 2 = 0.95 and Q 2 = 0.87 in the atom‐based model and R 2 = 0.901 and Q 2 = 0.77 in the field‐based model. R‐group enumeration study generated novel 6426 compounds which was further screened through virtual screening study. The top‐scoring compound was M1 with the highest docking score (−8.804 kcal/mol) where hydroxy amide is important for interaction with HDAC1 protein. The ADME analysis demonstrated the compound's drug‐like characteristics. Overall, all hit compounds showed pharmacokinetic characteristics found within the range that is considered safe for human usage. This study findings have the potential to be applied further in the development of HDAC1 inhibitors for the treatment of gastric cancer.