Combined Ligand and Fragment‐based Drug Design of Selective Histone Deacetylase – 6 Inhibitors

Petković, Miloš; Agbaba, Danica; Ganesan, A.; Nikolic, Katarina

doi:10.1002/minf.201800083

Cited by 18 publications

(6 citation statements)

References 59 publications

(107 reference statements)

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“…It is proposed that every pharmacophoric feature (chemistry of the ZBG, linker and CAP group) contributes to the selectivity of the HDAC6 inhibitors (55). Computational (56,57) and experimental (44,45) studies published in our group show that both the alkylhydroxamates (8,9) and phenylhydroxamates (10) may inhibit the HDAC6 isoform selectively (Figure 7). Apart from hydroxamic acid derivatives, 3-hydroxypyridin-2-thiones (11) are reported as ZBG which specifically inhibits the HDAC6 isoform (60).…”

Section: Selective Class Iib Hdac Inhibitorsmentioning

confidence: 94%

Medicinal chemistry of histone deacetylase inhibitors

Đoković¹,

Nikolić²,

Vujić³

2021

Arhiv za farmaciju

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Today, we are witnessing an explosion of scientific concepts in cancer chemotherapy. It has been considered for a long time that genetic instability in cancer should be treated with drugs that directly damage the DNA. Understanding the molecular basis of malignant diseases shed light on studying phenotypic plasticity. In the era of epigenetics, many efforts are being made to alter the aberrant homeostasis in cancer without modifying the DNA sequence. One such strategy is modulation of the lysine acetylome in human cancers. To remove the acetyl group from the histones, cells use the enzymes that are called histone deacetylases (HDACs). The disturbed equilibrium between acetylation and deacetylation on lysine residues of histones can be manipulated with histone deacetylase inhibitors (HDACi). Throughout the review, an effort will be made to present the mechanistic basis of targeting the HDAC isoforms, discovered selective HDAC inhibitors, and their therapeutical implications and expectations in modern drug discovery.

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Section: Selective Class Iib Hdac Inhibitorsmentioning

confidence: 94%

Medicinal chemistry of histone deacetylase inhibitors

Đoković¹,

Nikolić²,

Vujić³

2021

Arhiv za farmaciju

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“…The main idea in designing novel HDACi was to employ the 1-benzhydryl piperazine as a CAP group. Computational fragment-based screening reported in our previous study identified many interesting CAP groups for the design of HDAC6 inhibitors [32] . We used 1-benzhydryl piperazine as a template to calculate the total Surface Area (SAtot) and McGowan Volume (Vx) in the Dragon v. 6.0.7.…”

Section: Design and Synthesis Of Hdac Inhibitorsmentioning

confidence: 97%

Discovery of 1-benzhydryl piperazine-based HDAC inhibitors with anti-cancer and anti-metastatic properties against human breast cancer: synthesis, molecular modeling, in vitro and in vivo biological evaluation

Petković

Djoković

Santibanez

et al. 2022

Preprint

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Isoform-selective histone deacetylase (HDAC) inhibition is promoted as a rational strategy to develop safer anti-cancer drugs compared to non-selective HDAC inhibitors. Despite this presumed benefit, considerably more non-selective HDAC inhibitors have undergone clinical trials. In this report, we detail the design and discovery of potent HDAC inhibitors with 1-benzhydryl piperazine as a surface recognition group that differ in hydrocarbon linker. Surprisingly, in vitro HDAC screening identified two selective HDAC6 inhibitors (6b, IC50 = 186 nM and 9b, IC50 = 31 nM), as well as two non-selective nanomolar HDAC inhibitors (7b and 8b). The influence of linker chemistry of synthesized inhibitors on HDAC6 potency was studied using structure-based molecular modelling. The breast cancer cell-lines (MDA-MB-231 and MCF-7) were used to evaluate compound mediated in vitro anti-cancer, anti-migratory, and anti-invasive activities, leading to 8b as the most promising compound. In our study, 8b is identified as the HDAC inhibitor with very potent anti-angiogenic, anti-metastatic and anti-tumor effects in zebrafish MDA-MB-231 xenograft models at low micromolar concentrations.

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“…By utilizing crystal structures of human isoforms to support virtual docking studies and the development and comparison of three-dimensional quantitative structure−activity relationship (3D-QSAR) models for inhibitors, this strategy is implemented. 183 New inhibitors have also been developed utilizing a machine-learning-based multiconformational virtual screening strategy. Pharmacophore modeling, molecular dynamic simulation, molecular docking, fragment-based drug design, and virtual screening are all components of this method.…”

Section: Molecular Dynamic Simulationmentioning

confidence: 99%

Deciphering the Lexicon of Protein Targets: A Review on Multifaceted Drug Discovery in the Era of Artificial Intelligence

Nandi,

Bhaduri,

Das

et al. 2024

Mol. Pharmaceutics

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Understanding protein sequence and structure is essential for understanding protein−protein interactions (PPIs), which are essential for many biological processes and diseases. Targeting protein binding hot spots, which regulate signaling and growth, with rational drug design is promising. Rational drug design uses structural data and computational tools to study protein binding sites and protein interfaces to design inhibitors that can change these interactions, thereby potentially leading to therapeutic approaches. Artificial intelligence (AI), such as machine learning (ML) and deep learning (DL), has advanced drug discovery and design by providing computational resources and methods. Quantum chemistry is essential for drug reactivity, toxicology, drug screening, and quantitative structure−activity relationship (QSAR) properties. This review discusses the methodologies and challenges of identifying and characterizing hot spots and binding sites. It also explores the strategies and applications of artificial-intelligence-based rational drug design technologies that target proteins and protein−protein interaction (PPI) binding hot spots. It provides valuable insights for drug design with therapeutic implications. We have also demonstrated the pathological conditions of heat shock protein 27 (HSP27) and matrix metallopoproteinases (MMP2 and MMP9) and designed inhibitors of these proteins using the drug discovery paradigm in a case study on the discovery of drug molecules for cancer treatment. Additionally, the implications of benzothiazole derivatives for anticancer drug design and discovery are deliberated.

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Combined Ligand and Fragment‐based Drug Design of Selective Histone Deacetylase – 6 Inhibitors

Cited by 18 publications

References 59 publications

Medicinal chemistry of histone deacetylase inhibitors

Medicinal chemistry of histone deacetylase inhibitors

Discovery of 1-benzhydryl piperazine-based HDAC inhibitors with anti-cancer and anti-metastatic properties against human breast cancer: synthesis, molecular modeling, in vitro and in vivo biological evaluation

Deciphering the Lexicon of Protein Targets: A Review on Multifaceted Drug Discovery in the Era of Artificial Intelligence

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