Integrating Structure and Ligand-Based Approaches for Modelling the Histone Deacetylase Inhibition Activity of Hydroxamic Acid Derivatives

Abstract

Objective: Structure and ligand-based drug design approaches have be been integrated to accurately predict the inhibition activity of hydroxamic acid (HA) derivatives against the histone deacetylase-2 enzyme (HDAC2). Methods:The "active conformations" of the ligands in the binding site of the enzyme were determined by docking assays. More than 1000 0-3 dimensional molecular descriptors included in Dragon package were calculated and utilized for developing quantitative structure-activity relationship (QSAR) models through a multiple linear regression approach coupled with the genetic algorithm (GA-MLR). Results:The final model obtained showed suitable robustness and stability, with low correlation between descriptors and good predictive power. QSAR model was then used for screening bioactivity from a series of 36 novel HAs and found five candidates with very good bioactivity (half maximal inhibitory concentration<0.1 μM). Docking experiment revealed the binding mode of these compounds into the active site of HDAC2. Druglikeness and toxicity profiles of the compounds were checked through chemoinformatics tools. Conclusion:The results from this study can lead to rational design and synthesis of highly selective and potent HDAC2 inhibitors.

Novel (E)-3-(1-substituted-1H-indazol-5-yl)-N-hydroxypropenamides as histone deacetylase inhibitors: design, synthesis and structure–activity relationships

“…49 The protein structures were prepared by eliminating the ligand and water molecules, setting an appropriated force field, and fixing the atom types and protonation states of important residues surrounding the cofactor zinc ion. 50 Redocking the co-crystal ligand of these proteins was used to validate the docking procedure. Docking simulations with flexible ligands and rigid proteins, we set the MOE Triangle Matcher placement method and retained 30 poses for conformational analysis.…”

Novel (E)‐3‐(3‐Oxo‐4‐substituted‐3,4‐dihydro‐2H‐benzo[b][1,4]oxazin‐6‐yl)‐N‐hydroxypropenamides as Histone Deacetylase Inhibitors: Design, Synthesis and Bioevaluation

“…Then, R studio was employed to align downloaded amino acid strings and visualized using the ggmsa package developed by Zhou et al [46] The protein structures were prepared by setting appropriated force field, removing all the water molecules, adding polar hydrogen atoms, and editing important residues surrounding the cofactor Zinc ion. [47] For the docking methodology, 1000 conformations were generated using Triangle Matcher placement method then scored by London scoring function to have 30 poses retained. The type of post-placement refinement was Rigid receptor and the binding free energies dG (kcal/mol) were computed based on two functions: London and Affinity scoring implemented into MOE software.…”

Stability Constant and Potentiometric Sensitivity of Heavy Metal–Organic Fluorescent Compound Complexes: QSPR Models for Prediction and Design of Novel Coumarin-like Ligands

“…+ α n X n . The optimization approach based on the genetic algorithm (GA) was used for descriptor selection and to calculate the linear parameters of the MLR models [66]. The GA-MLR is based on the principles of evolution in biology, which seeks optimal models by iteratively modifying a set of randomly generated variable combinations using genetic operators, i.e., crossover, mutation, etc.…”