In silico Design of Novel Histone Deacetylase 4 Inhibitors: Design Guidelines for Improved Binding Affinity

Abstract

Histone deacetylases (HDAC) are being targeted for a number of diseases such as cancer, inflammatory disease, and neurological disorders. Within this family of 18 isozymes, HDAC4 is a prime target for glioma, one of the most aggressive brain tumors reported. Thus, the development of HDAC4 inhibitors could present a novel therapeutic route for glioma. In this work, molecular docking studies on cyclopropane hydroxamic acid derivatives identified five novel molecular interactions to the HDAC4 receptor that could be harnessed to enhance inhibitor binding. Thus, design guidelines for the optimization of potent HDAC4 inhibitors were developed which can be utilized to further the development of HDAC4 inhibitors. Using the developed guidelines, eleven novel cyclopropane hydroxamic acid derivatives were designed that outcompeted all original cyclopropane hydroxamic acids HDAC4 inhibitors studied in silico. The results of this work will be an asset to paving the way for further design and optimization of novel potent HDAC4 inhibitors for gliomas.

Optimization Rules for SARS-CoV-2 Mpro Antivirals: Ensemble Docking and Exploration of the Coronavirus Protease Active Site

“…Aromatic versus aliphatic structures can make significant changes in binding affinity to protein receptors. In the design of glioblastoma therapeutics targeting histone deacetylase 4 (HDAC4) inhibitors, it was determined that aliphatic substituents increased the potency of these compounds to the HDAC4 receptor [28]. Thus, in this study the impact of aromaticity versus aliphatic character was also evaluated.…”

“…Some docking studies have been performed on already available drug compounds to rank their potential for development as antiviral agents [20,21]. Studies using molecular docking have been utilized to analyze binding interactions of antiviral compounds targeting; the HIV protease [22,23], topoisomerase II DNA gyrase enzymes [24,25], and anti-cancer compounds which target histone deacetylases [26][27][28] and a range of other diseases can assist in the optimization of molecular interactions for drug design. Studies performed to explore the broad substrate binding preferences that SARS-CoV-2 M pro has would therefore significantly assist in the optimization of any lead drug compounds that are being pursued.…”

In Silico Design of Peptide-Based SARS-CoV-2 Fusion Inhibitors That Target WT and Mutant Versions of SARS-CoV-2 HR1 Domains

“…Additionally, molecular docking was used to predict the binding of the EK1 peptide to the WT SARS-CoV-2 HR1 and characterize the binding interactions of the EK1 peptide inhibitor to the WT SARS-CoV-2 HR1 domain; a complex that has not yet been crystallized. Molecular docking which can be used to identify how two molecules interact with each other greatly assists in optimization work [27,[35][36][37][38][39]. Molecular docking was used in this work to optimize the binding interactions between the WT SARS-CoV-2 HR1 domain and peptide inhibitors, followed by molecular dynamics simulations to predict binding affinities of our top antiviral designs.…”

Missense substitutions at a conserved 14-3-3 binding site in HDAC4 cause a novel intellectual disability syndrome

“…While a number of HDAC inhibitors are available for pharmacological use, class IIa HDACs are in fact poor responders to these drugs due to the lower deacetylase activity of these enzymes compared to other HDACs. 34 Effective therapy would therefore require development of inhibitors with specificity for class IIa enzymes (and preferably HDAC4 alone); a recent study reported the development of improved cyclopropane hydroxamic acid derivatives for inhibition of HDAC4 deacetylase activity, 35 while an alternative approach has been to target the interaction with MEF2. 36 …”