Structure-Based Prioritization of Heterocyclic Candidates Targeting HDAC8 through Molecular Docking, Molecular Dynamics, and ADMET Profiling

Abstract

The epigenetic target of growing interest in the discovery of anticancer drugs is the histone deacetylase 8 (HDAC8). The paper tested 14 heterocyclic (L1-L14) designs with an integrated computational workflow that included molecular docking, molecular dynamics (MD), ADME profiling and toxicity prediction. The docking of human HDAC8 (PDB ID: 1T69) resulted in L2 being the highest ranked compound by score (-5.954 kcal/mol), with L9 close behind (-5.881 kcal/mol) along with a predicted interaction with the catalytic Zn²⁺ center (2.31 Å). According to this binding geometry, L9 was prioritized for a 100-ns MD simulation. Following initial structural relaxation, the pathway facilitated further association of L9 to HDAC8 pocket by limited ligand-pocket separation, long-term hydrophobic interactions, and repeated yet discontinuous Zn378-O contact geometry. The geometric definition of the metal-contact analysis was based on the non-bonded Zn²⁺ representation used in the simulation and thus was perceived as recurrent metal-proximal interaction instead of a permanent zinc-chelation state. ADME analysis revealed that there were no Lipinski violations throughout the series, but solubility, polarity, and predicted gastrointestinal absorption among the candidates varied. L9 showed medium predicted solubility and low lipophilicity, as well as high topological polar surface area and low predicted gastrointestinal absorption. Various endpoint-specific alerts were produced in toxicity modeling of L9. Altogether, the combined findings support L9 as a high-ranking, mechanistically informative HDAC8-targeting candidate to be optimized through the designed series using structure-guided optimization.