Searching for newer histone deacetylase ۶ inhibitors: Design, ADMET prediction, molecular docking, and molecular dynamics simulation of new Isatin hydrazones

Background: HDAC۶ is distinctive among histone deacetylases (HDACs) due to its unique structural characteristics and catalytic domains. The targeted inhibition of HDAC۶ 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 HDAC۶ 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 ۳.۰. Molecular docking studies were performed with Autodock۴Zn, integrated within Amdock v۱.۵.۲, focusing on HDAC۶, HDAC۸, and HDAC۲. Additionally, a molecular dynamics simulation spanning ۱۰۰ 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 = ۰.۵۰۴, compounds ۹a and ۹b) and qualitative criteria for drug-likeness. Their ADMET analysis has revealed a favorable absorption parameter (highest Caco۲ permeability -۴.۹۵ log cm/s, ۹b), 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 HDAC۶ than HDAC۸ and HDAC۲ (except compounds ۹c and ۱۰a), where compound ۹a had the highest G (-۷.۹۱ Kcal/mol). Compounds ۹c and ۱۰a demonstrate a novel binding mode to HDAC۲, coordinating Zn۲+ through the isatin-hydrazone nucleus and contributing to its greater affinity to HDAC۲ (G = -۱۱.۲۳ and -۷.۹۹ Kcal/mol, respectively). In molecular dynamics simulation, compounds ۹a and ۹c have shown a stable binding to HDAC۶ and HDAC۲, respectively, maintaining their coordination with Zn۲+ throughout the simulation time. Conclusion: Our findings have revealed that the newly designed compounds have proper ADMET, binding affinity, and selectivity to HDAC۶, making them suitable candidates for further analysis. Remarkably, two compounds exhibited a novel binding to HDAC۲, potentially paving the way for a new zinc-binding group.

کلیدواژه ها:

Isatin-Hydrazone ، HDAC۶ ، HDAC۲ ، Amdock ، Autodock۴Zn ، Molecular Dynamics Simulation