Design, Synthesis, and biological evaluation of HDAC6 inhibitors based on Cap modification strategy

Li, Xuedong; Liu, Xingang; Wang, Songsong; Shi, Xiaoxing; Lu, Ming; Hao, Xinyue; Fu, Yan; Zhang, Yang; Jia, Qingzhong; He, Deyan

doi:10.1016/j.bioorg.2022.105874

Cited by 8 publications

(2 citation statements)

References 66 publications

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“…Discovery Studio 2020 (DS-2020) was used for the prediction of binding sites and molecular docking. The required Kv7.2 crystal was derived from Protein Data Five-thousand steps each of the steepest descent method and conjugate gradient method were applied to minimize the energy of constructed systems (Li et al, 2022;Zhang et al, 2020). Finally, a 100-ns MD simulation was carried out in the NPT ensemble and conformational and energetic analyses were conducted based on the resulting MD trajectory files.…”

Section: Computational Simulationmentioning

confidence: 99%

Modulation of Kv7 Channel Currents by Echinocystic Acid

Geng

Zheng

et al. 2023

Molecular Pharmacology

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Modulation of KCNQ-encoded voltage-gated potassium Kv7/M channel function represents an attractive strategy to treat neuronal excitability disorders such as epilepsy, pain, and depression. The Kv7 channel group includes five subfamily members (Kv7.1-7.5). Pentacyclic triterpenes display extensive pharmacological activities including anti-tumor, anti-inflammatory, and anti-depression effects. In this study, we investigated the effects of pentacyclic triterpenes on Kv7 channels. Our results show that echinocystic acid, ursonic acid, oleanonic acid, demethylzeylasteral, corosolic acid, betulinaldehyde, acetylursolic acid, and ⍺-boswellic acid gradually exert decreasing degrees of Kv7.2/Kv7.3 channel current inhibition. Echinocystic acid was the most potent inhibitor, with a half-maximal inhibitory concentration (IC 50 ) of 2.5 µM. It significantly shifted the voltage-dependent activation curve in a positive direction and slowed the time constant of activation for Kv7.2/Kv7.3 channel currents.Furthermore, echinocystic acid non-selectively inhibited Kv7.1-Kv7.5 channels.Taken together, our findings indicate that echinocystic acid is a novel and potent inhibitor that could be used as a tool to further understand the pharmacological functions of neuronal Kv7 channels.

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Section: Computational Simulationmentioning

confidence: 99%

Modulation of Kv7 Channel Currents by Echinocystic Acid

Geng

Zheng

et al. 2023

Molecular Pharmacology

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“…Thus, the design and synthesis of selective HDAC6 inhibitors have received widespread attention. − Selective HDAC6 inhibitors satisfied the classic pharmacophore model and are mainly composed of three parts: (1) the cap group (Cap) that occupies the rim region of a catalytic pocket; (2) the linker moiety (Linker) interacting with the residues in the hydrophobic pocket; (3) zinc binding group (ZBG) chelating with the zinc ion (Zn 2+ ) locating at the bottom of the pocket (Figure ). Based on the in-depth analysis of characteristics of the HDAC6 active pocket, the residues located on the rim of the active pocket were nonconservative, and the channel appeared wider and shallower than that of the HDAC1 subtype. − Therefore, the interactions between the Cap and the key residues in the active pocket affected the binding conformations and target affinity of the compounds, thereby causing the compounds to produce a certain degree of subtype-selective inhibitory activities. Therefore, among the molecular design strategies of selective HDAC6 inhibitors, Cap-based fragment optimization (especially amplification of Cap) was an important strategy, taking Tubastatin A ( TubA ) and ACY-1215 as examples .…”

Section: Introductionmentioning

confidence: 99%

Discovery of Potent Selective HDAC6 Inhibitors with 5-Phenyl-1H-indole Fragment: Virtual Screening, Rational Design, and Biological Evaluation

Li,

Wang,

Chai

et al. 2024

J. Chem. Inf. Model.

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Among the HDACs family, histone deacetylase 6 (HDAC6) has attracted extensive attention due to its unique structure and biological functions. Numerous studies have shown that compared with broad-spectrum HDACs inhibitors, selective HDAC6 inhibitors exert ideal efficacy in tumor treatment with insignificant toxic and side effects, demonstrating promising clinical application prospect. Herein, we carried out rational drug design by integrating a deep learning model, molecular docking, and molecular dynamics simulation technology to construct a virtual screening process. The designed derivatives with 5-phenyl-1H-indole fragment as Cap showed desirable cytotoxicity to the various tumor cell lines, all of which were within 15 μM (ranging from 0.35 to 14.87 μM), among which compound 5i had the best antiproliferative activities against HL-60 (IC 50 = 0.35 ± 0.07 μM) and arrested HL-60 cells in the G0/G1 phase. In addition, 5i exhibited better isotype selective inhibitory activities due to the potent potency against HDAC6 (IC 50 = 5.16 ± 0.25 nM) and the reduced inhibitory activities against HDAC1 (selective index ≈ 124), which was further verified by immunoblotting results. Moreover, the representative binding conformation of 5i on HDAC6 was revealed and the key residues contributing 5i's binding were also identified via decomposition free-energy analysis. The discovery of lead compound 5i also indicates that virtual screening is still a beneficial tool in drug discovery and can provide more molecular skeletons with research potential for drug design, which is worthy of widespread application.

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Discovery of selective HDAC6 inhibitors based on a multi-layer virtual screening strategy

Liu

Yan

et al. 2023

Computers in Biology and Medicine

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Design, Synthesis, and biological evaluation of HDAC6 inhibitors based on Cap modification strategy

Cited by 8 publications

References 66 publications

Modulation of Kv7 Channel Currents by Echinocystic Acid

Modulation of Kv7 Channel Currents by Echinocystic Acid

Discovery of Potent Selective HDAC6 Inhibitors with 5-Phenyl-1H-indole Fragment: Virtual Screening, Rational Design, and Biological Evaluation

Discovery of selective HDAC6 inhibitors based on a multi-layer virtual screening strategy

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