Identification of potential isoform-selective histone deacetylase inhibitors for cancer therapy: a combined approach of structure-based virtual screening, ADMET prediction and molecular dynamics simulation assay

Abstract

Histone deacetylases (HDACs) have gained increased attention as targets for anticancer drug design and development. HDAC inhibitors have proven to be effective for reversing the malignant phenotype in HDAC-dependent cancer cases. However, lack of selectivity of the many HDAC inhibitors in clinical use and trials contributes to toxicities to healthy cells. It is believed that, the continued identification of isoform-selective inhibitors will eliminate these undesirable adverse effects - a task that remains a major challenge to HDAC inhibitor designs. Here, in an attempt to identify isoform-selective inhibitors, a large compound library containing 2,703,000 compounds retrieved from Otava database was screened against class I HDACs by exhaustive approach of structure-based virtual screening using rDOCK and Autodock Vina. A total of 41 compounds were found to show high-isoform selectivity and were further redocked into their respective targets using Autodock4. Thirty-six compounds showed remarkable isoform selectivity and passed drug-likeness and absorption, distribution, metabolism, elimination and toxicity prediction tests using ADMET Predictor™ and admetSAR. Furthermore, to study the stability of ligand binding modes, 10 ns-molecular dynamics (MD) simulations of the free HDAC isoforms and their complexes with respective best-ranked ligands were performed using nanoscale MD software. The inhibitors remained bound to their respective targets over time of the simulation and the overall potential energy, root-mean-square deviation, root-mean-square fluctuation profiles suggested that the detected compounds may be potential isoform-selective HDAC inhibitors or serve as promising scaffolds for further optimization towards the design of selective inhibitors for cancer therapy.

The potential effects of clinical antidiabetic agents on SARS‐CoV‐2

“…Here we established the receptor‐based virtual screening approach for the potential inhibitor of M pro . Compared with the standard assay that was used to test whether the existing hypoglycemic drugs are effective in treating the viral infections, 32 our method could quickly and with high throughput screen drugs for repurposing or easily obtained compounds and shorten the time for new drug development 33,34 …”

Class I histone deacetylase inhibition by aryl butenoic acid derivatives: In silico and in vitro studies

“…Besides, deacetylation of non-histone proteins makes HDACs as popular therapeutic targets to modify different biological processes. Therefore, several molecules have been identified or developed as selective/non-selective inhibitors of HDACs [25][26][27][28][29]. Depending on chemical structures, these inhibitors interact with HDACs differently, which affects their potencies, toxicities and eventually efficacies.…”

Structure-Based Inhibitor Discovery of Class I Histone Deacetylases (HDACs)

“…Low toxicity and easy synthesis are the main features of aliphatic carboxylic acids [ 19 , 106 ]. The specific mechanism of them is not yet clear, most probably through binding to the active site [ 112 ]. A docking study also inferred that they might occupy the substrate-binding tunnel as general pan-inhibitors do [ 113 ].…”

“…A problem with the currently available pan-HDAC inhibitors is that they have limited specificity and target multiple deacetylases, greatly limiting their clinical uses due to significant side effects [ 117 ]. The design of isoform-selective inhibitors has become the main focus and is being actively undertaken [ 112 , 117 , 118 ]. Here, we introduce the current status of selective inhibitor development according to their targeted isoforms.…”