Molecular docking, dynamics, and ADME studies of new isatin derivatives as histone deacetylase (HDAC) inhibitors

Abstract

Histone deacetylase-2 (HDAC-2) is an important therapeutic target in cancer treatment. Isatin derivatives have attracted considerable interest in medicinal chemistry because of their diverse biological activities. The present study aimed to investigate a series of newly designed isatin derivatives as HDAC-2 inhibitors using computational approaches. Molecular docking was performed against HDAC-2 protein (3MAX) to evaluate the binding affinity and interactions of the proposed compounds. ADME analysis was performed to assess their pharmacokinetic and drug-likeness properties. The most promising derivative was subjected to molecular dynamics (MD) simulation for 200 ns to evaluate the stability of the protein–ligand complex and characterize key molecular interactions throughout the simulation period. Among the investigated compounds, Compound 2 exhibited the most favorable binding affinity toward HDAC-2 with a docking score of -9.866 kcal/mol, slightly exceeding that of the reference inhibitor SAHA -9.707 kcal/mol. The compound demonstrates stable interactions with binding site residues and maintained interaction with zinc ion. MD simulations demonstrated stable protein-ligand interactions, minimum structural fluctuations, and preservation of the overall protein secondary structure throughout the simulation. These findings suggest that Compound 2 could be a promising isatin-based scaffold for the development of new HDAC-2 inhibitors.