Abstract 4465: Molecular docking studies on the factors affecting histone deacetylase inhibition: Design, rigidity, and chirality of the inhibitors

Abstract Histone deacetylase (HDAC) has become one of the targets for cancer therapy since it was found overexpressed in cancer cells. New HDAC inhibitors were designed and investigated to demonstrate how the molecules interact with HDAC enzymes, using the molecular docking software ICM-Pro. Multiple families of HDAC inhibitors, derivatized from the FDA-approved HDAC inhibitors, were constructed and optimized for in silico screening. Detailed analyses of the docking results showed that the addition of an aromatic ring on the linker domain could boost or diminish the interactions of the molecules with the enzyme, depending on the location and size of the aromatic ring. The rigidity of the molecules was tuned by installing heterocyclic rings of various sizes at different positions. Molecules of specific rigidity could greatly enhance the dock scores and binding affinity, thus theoretically the enzyme inhibition. Modification of protein recognition and zinc-binding domains and chirality of the molecules were also explored to seek inhibitors for specific HDAC inhibitions. Drug candidates with the desired binding affinity and selectivity were selected for chemical synthesis and biological activity examination in the lab. Citation Format: Qinliang Zhao, Jacquelyn Ann Tang, Karina Artero, Audrey Huang, Rabeya Bosri. Molecular docking studies on the factors affecting histone deacetylase inhibition: Design, rigidity, and chirality of the inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4465.