Computationally Guided Design of New Naphthalene-Oxazole-Hydrazone Derivatives as Potential HDAC Inhibitors: ADME Assessment, Molecular Docking, Molecular Dynamics, and MM/GBSA Analysis

Abstract

Histone deacetylases (HDACs) are important therapeutic targets in cancer because of their central role in epigenetic regulation. Although several hydroxamate-based HDAC inhibitors have reached clinical use, their limited selectivity and unfavourable pharmacokinetic properties have encouraged the development of alternative non-hydroxamate scaffolds. In this study, three novel naphthalene–oxazole–hydrazone derivatives (5a–5c) were rationally designed as potential non-hydroxamate HDAC inhibitors. Their drug-likeness and pharmacokinetic properties were evaluated using Swiss ADME, while molecular docking was performed against HDAC2 (PDB IDs: 3MAX and 5IX0) and HDAC8 (PDB ID: 1T69) using Schrödinger Suite 2024. The most promising protein–ligand complexes were further investigated by 200 ns molecular dynamics simulations followed by MM/GBSA binding free-energy calculations. The docking study revealed that compounds 5b and 5c exhibited stronger predicted binding affinities than the reference inhibitor vorinostat toward most investigated HDAC isoforms according to the molecular docking calculations. Molecular dynamics simulations predicted stable protein–ligand complexes with acceptable RMSD and RMSF profiles throughout the simulation period, whereas MM/GBSA calculations supported favourable binding free energies, particularly for compound 5c against HDAC2 (3MAX). In addition, all designed compounds satisfied Lipinski's rule of five and exhibited favourable predicted ADME characteristics. These computational findings suggest that the designed naphthalene–oxazole–hydrazone derivatives, especially compound 5c, emerged as the most promising candidate among the designed derivatives based on the computational analyses that warrant further synthesis and biological evaluation.