In the quest for histone deacetylase inhibitors: current trends in the application of multilayered computational methods

Uba, Abdullahi Ibrahim; Zengin, Gökhan

doi:10.1007/s00726-023-03297-y

Cited by 6 publications

(2 citation statements)

References 137 publications

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“…Pharmacophore models can be classified as structure-based, developed from protein-ligand complexes, or ligand-based, utilizing known HDAC inhibitors' structures. These models undergo validation to ensure their efficacy in distinguishing active and inactive compounds, often through methods like Receiver Operating Characteristic (ROC) analysis or inactive compounds (decoy) testing [221]. For instance, in the search of potential selective inhibitors targeting HDAC2, a screening process was conducted on 300,000 compounds sourced from Asinex, National Cancer Institute (NCI) and Maybridge databases using e-pharmacophore modeling [222].…”

Section: Molecular Modelingmentioning

confidence: 99%

The Histone Deacetylase Family: Structural Features and Application of Combined Computational Methods

Curcio,

Rocca,

Alcaro

et al. 2024

Pharmaceuticals

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Histone deacetylases (HDACs) are crucial in gene transcription, removing acetyl groups from histones. They also influence the deacetylation of non-histone proteins, contributing to the regulation of various biological processes. Thus, HDACs play pivotal roles in various diseases, including cancer, neurodegenerative disorders, and inflammatory conditions, highlighting their potential as therapeutic targets. This paper reviews the structure and function of the four classes of human HDACs. While four HDAC inhibitors are currently available for treating hematological malignancies, numerous others are undergoing clinical trials. However, their non-selective toxicity necessitates ongoing research into safer and more efficient class-selective or isoform-selective inhibitors. Computational methods have aided the discovery of HDAC inhibitors with the desired potency and/or selectivity. These methods include ligand-based approaches, such as scaffold hopping, pharmacophore modeling, three-dimensional quantitative structure–activity relationships, and structure-based virtual screening (molecular docking). Moreover, recent developments in the field of molecular dynamics simulations, combined with Poisson–Boltzmann/molecular mechanics generalized Born surface area techniques, have improved the prediction of ligand binding affinity. In this review, we delve into the ways in which these methods have contributed to designing and identifying HDAC inhibitors.

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Section: Molecular Modelingmentioning

confidence: 99%

The Histone Deacetylase Family: Structural Features and Application of Combined Computational Methods

Curcio,

Rocca,

Alcaro

et al. 2024

Pharmaceuticals

View full text Add to dashboard Cite

show abstract

“…Over the years, the development of HDAC inhibitors (HDACis) for cancer treatment has been a fruitful area of research [117,118]. To date, vorinostat, panobinostat, belinostat, romidepsin and chidamide are the only HDACis currently marketed for cancer treatment [119]. Several HDACis are also in clinical trials [120].…”

Section: Histone Deacetylase (Hdac) Inhibition Studiesmentioning

confidence: 99%

Platinum(IV) Prodrugs Incorporating an Indole-Based Derivative, 5-Benzyloxyindole-3-Acetic Acid in the Axial Position Exhibit Prominent Anticancer Activity

Aputen,

Elias,

Gilbert

et al. 2024

IJMS

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Kinetically inert platinum(IV) complexes are a chemical strategy to overcome the impediments of standard platinum(II) antineoplastic drugs like cisplatin, oxaliplatin and carboplatin. In this study, we reported the syntheses and structural characterisation of three platinum(IV) complexes that incorporate 5-benzyloxyindole-3-acetic acid, a bioactive ligand that integrates an indole pharmacophore. The purity and chemical structures of the resultant complexes, P-5B3A, 5-5B3A and 56-5B3A were confirmed via spectroscopic means. The complexes were evaluated for anticancer activity against multiple human cell lines. All complexes proved to be considerably more active than cisplatin, oxaliplatin and carboplatin in most cell lines tested. Remarkably, 56-5B3A demonstrated the greatest anticancer activity, displaying GI50 values between 1.2 and 150 nM. Enhanced production of reactive oxygen species paired with the decline in mitochondrial activity as well as inhibition of histone deacetylase were also demonstrated by the complexes in HT29 colon cells.

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Computer‐Aided Design of VEGFR‐2 Inhibitors as Anticancer Agents: A Review

Uba

2024

J of Molecular Recognition

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Due to its intricate molecular and structural characteristics, vascular endothelial growth factor receptor 2 (VEGFR‐2) is essential for the development of new blood vessels in various pathological processes and conditions, especially in cancers. VEGFR‐2 inhibitors have demonstrated significant anticancer effects by blocking many signaling pathways linked to tumor growth, metastasis, and angiogenesis. Several small compounds, including the well‐tolerated sunitinib and sorafenib, have been approved as VEGFR‐2 inhibitors. However, the widespread side effects linked to these VEGFR‐2 inhibitors—hypertension, epistaxis, proteinuria, and upper respiratory infection—motivate researchers to search for new VEGFR‐2 inhibitors with better pharmacokinetic profiles. The key molecular interactions required for the interaction of the small molecules with the protein target to produce the desired pharmacological effects are identified using computer‐aided drug design (CADD) methods such as pharmacophore and QSAR modeling, structure‐based virtual screening, molecular docking, molecular dynamics (MD) simulation coupled with MM/PB(GB)SA, and other computational strategies. This review discusses the applications of these methods for VEGFR‐2 inhibitor design. Future VEGFR‐2 inhibitor designs may be influenced by this review, which focuses on the current trends of using multiple screening layers to design better inhibitors.

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In the quest for histone deacetylase inhibitors: current trends in the application of multilayered computational methods

Cited by 6 publications

References 137 publications

The Histone Deacetylase Family: Structural Features and Application of Combined Computational Methods

The Histone Deacetylase Family: Structural Features and Application of Combined Computational Methods

Platinum(IV) Prodrugs Incorporating an Indole-Based Derivative, 5-Benzyloxyindole-3-Acetic Acid in the Axial Position Exhibit Prominent Anticancer Activity

Computer‐Aided Design of VEGFR‐2 Inhibitors as Anticancer Agents: A Review

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