Overall, this study identifies selected 4-oxoquinazoline hydroxamic acid derivatives as preliminary computational leads for further experimental validation as potential HDAC8-targeting compounds.
Abstract
Cancer remains a major global health challenge, highlighting the need for novel therapeutic agents with improved selectivity and efficacy. Histone deacetylase (HDAC) inhibition represents an important epigenetic strategy in anticancer drug discovery because it can influence gene expression, cell-cycle regulation, and tumor cell survival. In this computational study, fifteen 4-oxoquinazolin-3(4
H
)-yl-
N
-hydroxybenzamide derivatives were evaluated as potential HDAC8-targeting compounds using an integrated
in silico
workflow. Molecular docking was performed against HDAC8 using the crystal structure deposited under Protein Data Bank (PDB) ID 1T69, with suberoylanilide hydroxamic acid (SAHA) used as the reference inhibitor.
The investigated derivatives showed favorable accommodation within the HDAC8 catalytic pocket, with predicted interaction patterns involving zinc coordination, hydrogen bonding, and π-related interactions with key active-site residues. Several derivatives showed favorable predicted docking scores and interaction profiles relative to SAHA, suggesting that the designed quinazolinone–hydroxamate scaffold may be suitable for further prioritization. Prime molecular mechanics generalized Born surface area (MM-GBSA) analysis identified selected derivatives with comparatively favorable calculated binding free-energy contributions, particularly through van der Waals, electrostatic, and lipophilic interactions.
In silico
absorption, distribution, metabolism, and excretion (ADME) prediction indicated that most derivatives possessed acceptable drug-like and pharmacokinetic descriptors, including physicochemical properties, predicted oral absorption, and limited central nervous system (CNS) activity. Density functional theory (DFT) analysis provided supportive electronic-level information by identifying molecular regions that may contribute to hydrogen bonding and zinc coordination. A 100 ns molecular dynamics simulation of the HDAC8–derivative 15 complex suggested the short-timescale persistence of one representative predicted binding pose under the selected simulation conditions.
Overall, this study identifies selected 4-oxoquinazoline hydroxamic acid derivatives as preliminary computational leads for further experimental validation as potential HDAC8-targeting compounds.
Histone deacetylase 2 (HDAC2) is a promising epigenetic target for cancer therapy; however, the clinical utility of Vorinostat (SAHA) is limited by poor selectivity, toxicity, and inadequate blood–brain barrier (BBB) permeability. A structure–activity relationship (SAR)-guided strategy was employed to identify novel coumarin-based HDAC2 inhibitors. A total of 2555 PubChem coumarin derivatives were filtered using Lipinski's criteria, yielding 1879 drug-like molecules for docking against HDAC2 (PDB ID: 7ZZT). Seventeen lead compounds guided the design of 46 novel derivatives. Docking identified compounds with binding affinities of −7.0 to −9.3 kcal/mol, exceeding SAHA (−7.3 kcal/mol). SAR analysis highlighted the coumarin scaffold, an additional aromatic ring, a 3–6 atom linker, a furan bridge, and terminal hydroxyl or methoxy groups as key structural features. Compound C5 exhibited high functional similarity with SAHA (R
2
= 0.898), favorable BBB permeability, superior predicted HDAC2 inhibition (IC
50
= 0.560 µM vs. 1.116 µM), enhanced predicted antiproliferative activity against MCF7, MDA-MB-231, HL-60, and U87MG cell lines, and stable binding confirmed by steered and 100 ns molecular dynamics simulations, identifying Asp104 as a key stabilizing residue.
Unknown authors· Main group chemistry (Print)· 0 citations
HDAC inhibitors are used as anticancer drugs, and the Zn2+-coordinating hydroxamic acid moiety in the drug vorinostat (SAHA) plays a key role in the mode of action. The introduction of metal centers in the structures of HDAC inhibitors (HDACis) allows for additional interactions between the inhibitor and the protein. To alter the interactions between HDACs and half-sandwich organometallic HDACis, we introduced amphiphilic 1,3,5-triaza-7-phosphaadamantane (PTA) or lipophilic triphenylphosphine (PPh3) as coligands. The half-sandwich compounds were found to be stable in aqueous solution, and the Rh(III) derivatives exhibited promising antiproliferative and HDAC inhibitory activity compared to their chlorido precursor. The lipophilic Rh-PPh3 compound was effectively taken up into human cancer cells, where it caused α-tubulin hyperacetylation with low impact on the histone H3 acetylation level. Molecular docking studies revealed additional interactions on the surface of the protein due to the presence of the P-donor ligands. Coordination of a CoIII(cyclen) chaperone to the hydroxamic acid moiety yielded reduction-responsive heterobimetallic compounds in which the bioactivity of the hydroxamic acid moiety was effectively masked.
Chen Chen, Barbora Havlinova, M. Vošahlíková et al.· Inorganic Chemistry· 0 citations
Histone deacetylases (HDACs) are well-established therapeutic targets in cancer due to their critical roles in regulating histone acetylation, chromatin structure, and gene expression, which are associated with cell growth, differentiation, and apoptosis. This study aims to investigate the binding interactions of hydroxamic acid–based inhibitors against histone deacetylase-like protein (HDLP) using the MM-PBSA method, assess their structural stability, and evaluate their inhibitory potential, employing integrated computational approaches. In this study, SAHA and newly designed derivatives CHR3996, ACY1215, HAD1, and HAD5 were systematically evaluated using integrated in-silico drug discovery approaches. Molecular docking was performed to predict binding orientations, key intermolecular interactions, and relative binding affinities toward the HDLP enzyme. To further validate docking results, molecular dynamics simulations were performed to assess the structural stability, compactness, and conformational flexibility of the HDLP–inhibitor complexes under dynamic conditions. Trajectory analyses, including RMSD, radius of gyration, RMSF, solvent-accessible surface area, and Ramachandran plots, indicated improved stability and favourable conformational behaviour for complexes involving SAHA, CHR3996, ACY1215, HAD5, and HAD3. In addition, MM-PBSA binding free energy calculations confirmed that CHR3996, ACY1215, HAD5, and HAD3 exhibit stronger binding affinities compared to the remaining inhibitors. The inhibitory potential of the selected compounds was further assessed by theoretically estimating IC₅₀ values from docking-derived binding energies. ACY1215, CHR3996, and SAHA demonstrated the most potent inhibition with predicted nanomolar IC₅₀ values, whereas HAD2–HAD4 showed moderate to weak activity. Overall, these findings identify CHR3996, ACY1215, HAD5, and HAD3 as promising HDAC inhibitor candidates for further lead optimization, experimental validation, and preclinical anticancer drug development.
Parthiban Gunasingham, Dushanan Ramachandran, D. Dissanayake et al.· OUSL Journal· 0 citations
Quinoxaline is a versatile nitrogen-containing heteroaromatic scaffold with considerable potential in anticancer drug discovery because structural modifications of its fused benzene–pyrazine framework can produce compounds with diverse pharmacological activities. This review highlights recent advances in the anticancer potential of quinoxaline derivatives, emphasizing their broad molecular targets and structure–activity relationships (SAR). Quinoxaline-based compounds have demonstrated activity against topoisomerases, tubulin, DNA repair pathways, PARP, histone deacetylases, folate metabolism, reactive oxygen species, VEGFR-2, EGFR, HER2, c-Met, PI3K/Akt/mTOR, PIM kinases, BRD9, BET proteins, PFKFB3, and apoptosis- and metastasis-associated pathways. SAR studies demonstrate that substitution pattern, aromaticity, hydrogen-bonding capacity, electronic properties, linker configuration, and physicochemical characteristics strongly influence anticancer potency and selectivity. Emerging approaches include selective targeting of BRD9 and BD1, inhibition of PFKFB3, VEGFR-2 blockade in treatment-resistant tumors, and modulation of HIF-1α, VEGF, and p21. Despite these advances, most quinoxaline-based anticancer candidates remain at the preclinical stage, with limitations involving inconsistent experimental conditions, inadequate pharmacokinetic characterization, poor aqueous solubility, metabolic instability, and potential off-target toxicity. Future development should therefore emphasize target validation, structure-based optimization, advanced drug-delivery approaches, pharmacokinetic improvement, physiologically relevant disease models, and rational combination strategies. Overall, quinoxaline represents a flexible platform for developing multifunctional and target-directed anticancer agents with potential applications across diverse cancer-associated pathways.
Racha Umadevi, K. Sujatha, Medidi Srinivas· Adolescência e Saúde· 0 citations
Epigenetic drugs offered a novel disease therapeutic strategy by reversibly modulating gene expression. For instance, inhibitors targeting histone lysine demethylases (KDMs) and histone deacetylases (HDACs) demonstrated significant potential in combating complex diseases such as cancer and neurological diseases. However, single-target inhibitors often exhibit limited efficacy or resistance due to the complexity of disease mechanisms and the activation of compensatory pathways. To address these limitations, a series of novel quinazoline derivatives were designed and synthesized as potent dual inhibitors targeting histone lysine demethylase JMJD3 and histone deacetylases. Through systematic structural optimization, lead compound 6a was identified with nanomolar potency: JMJD3 (IC50 = 545 nM), HDAC1/2/3/6/10 (IC50 = 1.1/3.5/4.4/16/8.3 nM), along with significant selectivity over related isoforms including JMJD1B, JMJD2A and HDAC8. The cellular enzymatic inhibition activity was validated in triple-negative breast cancer (TNBC) cell lines MDA-MB-231 and HCC1806, where 6a dose-dependently elevated the levels of H3K27 methylation (me1/me2/me3) and H3 acetylation. The therapeutic potential of these JMJD3/HDAC inhibitors was further evaluated in TNBC cell models, where they exhibited potent antiproliferative activity and induced cell cycle arrest. Compared with previously reported JMJD3/HDAC dual inhibitors, 6a demonstrates superior nanomolar potency against both targets. As a highly potent lead, 6a provides a novel scaffold for dual-target epigenetic drug discovery, a valuable chemical probe for investigating epigenetic crosstalk, and a promising candidate for cancer therapy.
The MGC803 cell line is a human gastric cancer model frequently used in cancer research. In this context, a combined in silico approach including 3D-QSAR modeling, ADMET analysis, network pharmacology, docking, molecular dynamics and ligand transport evaluations, was applied to design new antiproliferative molecules. A robust 3D-QSAR model with high predictive capacity (R² and Q²) was developed and used to design new compounds (PR1–PR4). After an ADMET screening, the putative biological targets of the non-toxic compounds were predicted using PharmMapper. A network pharmacology analysis identified several hub genes, of which HSP90AA1 had the highest degree value. Given its central role in stabilizing multiple oncogenic proteins involved in gastric cancer progression, as well as its suitability for structure-based studies, HSP90AA1 was selected for molecular docking and molecular dynamics simulations. In addition, molecular docking was performed on HSP90AA1 protein (1YET) in complex with the designed molecules (PR1-PR4), and their predicted binding behaviors were compared to both the most active molecule (M34) and the reference drug, geldanamycin. These results demonstrate a high predicted binding affinity and remarkable interaction profiles within the active site of the HSP90AA1. To further evaluate the dynamic stability of these complexes, we performed molecular dynamics simulations over a 100 ns period, thus confirming stable attachment modes and durable contact networks. The MM-PBSA approach demonstrated favorable binding free energies between the chosen PR4 ligand and the 1YET protein (-26.47 ± 2.89 kcal/mol). Finally, the ligand transport study showed that the PR4 ligand easily crosses tunnels 1 and 2 with optimal theoretical transport dynamics compared to the reference drug, geldanamycin (GA). This comprehensive computational method underlines the diverse potential of the examined molecules, identifying the most promising candidates for subsequent experimental validation against gastric cancer.
L. Naanaai, Abdellah El Aissouq, Yassine El Allouche et al.· Beni-Suef University Journal...· 0 citations
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