DESIGN AND COMPUTATIONAL ANALYSIS OF NEW ISATIN-IMINE HYBRIDS AS SELECTIVE HDAC6 INHIBITORS

Objective: Emerging evidence highlights the critical role of Histone Deacetylase (HDAC) 6 in various pathologies, including cancer and neurodegenerative diseases. Therefore, we sought to computationally study new isatin-imine hybrid compounds to predict their Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) profiles and binding mode with HDAC6 through docking and molecular dynamics simulations. Methods: ADMET and drug-likeness properties of target compounds were predicted using ADMETlab 3.0. Molecular docking was conducted using Autodock4Zn embedded in Amdock v1.5.2 against HDAC6, HDAC8, and HDAC2. Utilizing Newton's equations of motion in conjunction with the Desmond package from the Schrödinger software suite, a molecular dynamics simulation of 100 nanoseconds was conducted to investigate protein-ligand interactions at the atomic level. Results: All compounds exhibited favorable physicochemical characteristics and met drug-likeness criteria, showing good absorption profile, high protein binding (except Km73 and Km74), and Human Liver Microsomal enzyme stability. Three compounds (Km66, Km68, and Km74) had low plasma clearance, while Km69, Km72, and Km73 had moderate clearance. Compounds were predicted to have favorable toxicity profiles. In docking studies on HDAC6, all compounds showed higher binding affinities (-7.44 to-10.69 Kcal/mol) than the reference compounds SAHA and Nexturastat A. For HDAC2, all compounds had a lower binding affinity than for HDAC6, except Km68, which showed a higher affinity for HDAC2 (-10.61 vs.-9.23 Kcal/mol). Km68 and Km69 demonstrated stable binding modes in molecular dynamics simulations, while Km68 showed some deviations. Conclusion: Our findings indicate that all compounds demonstrate favorable ADMET profiles, binding affinities, and selectivity towards HDAC6. Their predicted binding affinity has outperformed that of reference compounds, including SAHA and HDAC6-selective nexturastat A. This suggests that these compounds have the potential to be promising candidates for selective inhibition of HDAC6, thereby opening up new possibilities in drug development.