فهرست نشریات علمی دسترسی آزاد ایران

Background: HDAC6 is distinctive among histone deacetylases (HDACs) due to its unique structural characteristics and catalytic domains. The targeted inhibition of HDAC6 offers more potential benefits than the pan HDAC inhibitors. Objectives: Hence, this study aimed to perform a computational analysis of compounds designed to use isatin-hydrazone as a surface recognition group, to predict their ADMET characteristics, and to clarify their binding modes to HDAC6 and other HDACs through docking studies and molecular dynamics simulations. Methods: The ADMET and drug-likeness properties of the designed compounds were predicted using ADMETlab 3.0. Molecular docking studies were performed with Autodock4Zn, integrated within Amdock v1.5.2, focusing on HDAC6, HDAC8, and HDAC2. Additionally, a molecular dynamics simulation spanning 100 nanoseconds was conducted using the Desmond package from the Schrödinger software suite, applying Newton's equations of motion to explore protein-ligand interactions at the atomic level. Results: All designed compounds have shown a desirable physicochemical characteristic and have successfully met all the quantitative (QED = 0.504, compounds 9a and 9b) and qualitative criteria for drug-likeness. Their ADMET analysis has revealed a favorable absorption parameter (highest Caco2 permeability -4.95 log cm/s, 9b), distribution parameters, low-moderate plasma clearance, and a favorable toxicity profile. Regarding molecular docking, the designed compounds have shown a higher binding affinity (G) to HDAC6 than HDAC8 and HDAC2 (except compounds 9c and 10a), where compound 9a had the highest G (-7.91 Kcal/mol). Compounds 9c and 10a demonstrate a novel binding mode to HDAC2, coordinating Zn2+ through the isatin-hydrazone nucleus and contributing to its greater affinity to HDAC2 (G = -11.23 and -7.99 Kcal/mol, respectively). In molecular dynamics simulation, compounds 9a and 9c have shown a stable binding to HDAC6 and HDAC2, respectively, maintaining their coordination with Zn2+ throughout the simulation time. Conclusion: Our findings have revealed that the newly designed compounds have proper ADMET, binding affinity, and selectivity to HDAC6, making them suitable candidates for further analysis. Remarkably, two compounds exhibited a novel binding to HDAC2, potentially paving the way for a new zinc-binding group.