Computational Design of a Time-Dependent Histone Deacetylase 2 Selective Inhibitor

Zhou, Jingwei; Li, Min; Chen, Nanhao; Wang, Shenglong; Luo, Hao; Zhang, Yingkai; Wu, Ruibo

doi:10.1021/cb500767c

Cited by 40 publications

(38 citation statements)

References 46 publications

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“…27 Individual pharmacologic targeting of Hdac1 vs. Hdac2 is considered very difficult given the nearly identical nature of the their active sites and surrounding surfaces, but there are reports of small molecules that show different dissociation rates for Hdac1 vs. Hdac2; such kinetically-selective Hdac2 inhibitors enhance Treg function in vitro but have not been tested in vivo . 28, 29 An alternate approach is to target the functions of the HDAC-associated complex, though the core components and their partnering molecules may vary by cell type and function. 30 An example of this approach, in the case of the CoREST complex, was the development of dual inhibitors of the HDAC and demethylase activities of the complex, 31 and these inhibitors are under investigation for their effects on Tregs.…”

Section: Hdac Enzymes and Treg Cellsmentioning

confidence: 99%

Histone/protein deacetylase inhibitor therapy for enhancement of Foxp3+ T-regulatory cell function posttransplantation

Wang

Beier

Akimova

et al. 2018

American Journal of Transplantation

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T-regulatory (Treg) cells are like other cells present throughout the body in being subject to biochemical modifications in response to extracellular signals. An important component of these responses involves changes in posttranslational modifications (PTMs) of histones and many nonhistone proteins, including phosphorylation/dephosphorylation, ubiquitination/deubiquitination, and acetylation/deacetylation. Foxp3, the key transcription factor of Tregs, is constantly being rapidly turned over, and a number of these PTMs determine its level of expression and activity. Of interest in the transplant setting, modulation of the acetylation or deacetylation of key lysine residues in Foxp3 can promote the stability and function, leading to increased Treg production and increased Treg suppressive activity. This mini-review focuses on recent data concerning the roles that histone/protein deacetylases (HDACs) play in control of Treg function, and how small molecule HDAC inhibitors can be used to promote Treg-dependent allograft survival in experimental models. These data are discussed in the light of increasing interest in the identification and clinical evaluation of isoform-selective HDAC inhibitors, and their potential application as tools to modulate Foxp3+ Treg cell numbers and function in transplant recipients.

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Section: Hdac Enzymes and Treg Cellsmentioning

confidence: 99%

Histone/protein deacetylase inhibitor therapy for enhancement of Foxp3+ T-regulatory cell function posttransplantation

Wang

Beier

Akimova

et al. 2018

American Journal of Transplantation

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“…Despite of the fact that computational approaches toward the role of HDACi against ataxia is relatively young, sufficient data are present to indicate the possibility to discover and design novel HDAC inhibitors using pharmacophore based virtual screening approaches. An increasing large number of HDACi are being reported, chemo-informatical analyses of these reported HDACi allows researchers to analyze the chemical space occupied by HDAC's and to create filters that can be included in virtual screening experiments together with pharmacophores (Tang et al, 2009; Ganai et al, 2015; Zhou et al, 2015). …”

Section: Discussionmentioning

confidence: 99%

Mechanistic Insights into the Binding of Class IIa HDAC Inhibitors toward Spinocerebellar Ataxia Type-2: A 3D-QSAR and Pharmacophore Modeling Approach

et al. 2017

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Spinocerebellar ataxia (SCA-2) type-2 is a rare neurological disorder among the nine polyglutamine disorders, mainly caused by polyQ (CAG) trinucleotide repeats expansion within gene coding ataxin-2 protein. The expanded trinucleotide repeats within the ataxin-2 protein sequesters transcriptional cofactors i.e., CREB-binding protein (CBP), Ataxin-2 binding protein 1 (A2BP1) leading to a state of hypo-acetylation and transcriptional repression. Histone de-acetylases inhibitors (HDACi) have been reported to restore transcriptional balance through inhibition of class IIa HDAC's, that leads to an increased acetylation and transcription as demonstrated through in-vivo studies on mouse models of Huntington's. In this study, 61 di-aryl cyclo-propanehydroxamic acid derivatives were used for developing three dimensional (3D) QSAR and pharmacophore models. These models were then employed for screening and selection of anti-ataxia compounds. The chosen QSAR model was observed to be statistically robust with correlation coefficient (r2) value of 0.6774, cross-validated correlation coefficient (q2) of 0.6157 and co-relation coefficient for external test set (pred_r2) of 0.7570. A high F-test value of 77.7093 signified the robustness of the model. Two potential drug leads ZINC 00608101 (SEI) and ZINC 00329110 (ACI) were selected after a coalesce procedure of pharmacophore based screening using the pharmacophore model ADDRR.20 and structural analysis using molecular docking and dynamics simulations. The pharmacophore and the 3D-QSAR model generated were further validated for their screening and prediction ability using the enrichment factor (EF), goodness of hit (GH), and receiver operating characteristics (ROC) curve analysis. The compounds SEI and ACI exhibited a docking score of −10.097 and −9.182 kcal/mol, respectively. An evaluation of binding conformation of ligand-bound protein complexes was performed with MD simulations for a time period of 30 ns along with free energy binding calculations using the g_mmpbsa technique. Prediction of inhibitory activities of the two lead compounds SEI (7.53) and ACI (6.84) using the 3D-QSAR model reaffirmed their inhibitory characteristics as potential anti-ataxia compounds.

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“…27 In recent years, there has been a growing interest in the discovery of time-dependent selective inhibitors. 80,81 Covalent interaction with the target protein offers significant pharmacological advantages. Covalent ligand−target interac-…”

Section: Conclusion and Prospectsmentioning

confidence: 99%

Strategies for the Discovery of Target-Specific or Isoform-Selective Modulators

et al. 2015

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Currently, the creation of class- and isoform-selective modulators of biologically important targets is a particularly challenging problem because different isoforms within a protein family often show striking similarity in spatial quaternary structure, especially at the catalytic sites or binding pockets. Therefore, an understanding of both the precise three-dimensional structure of the target protein and the mechanisms of action of modulators is important for developing more effective and selective agents. In this Perspective, we discuss currently available rational design strategies for obtaining class- and isoform-selective inhibitors and we illustrate these strategies with the aid of specific examples from the recent literature. The strategies covered include: (1) target-derived (-dependent) de novo drug discovery methodologies, and (2) follow-on derivatization approaches from initially identified active molecules (hit-to-lead and lead-to-candidate efforts). We also comment on prospects for further development and integration of strategies to achieve target-specific or isoform-selective inhibition.

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Computational Design of a Time-Dependent Histone Deacetylase 2 Selective Inhibitor

Cited by 40 publications

References 46 publications

Histone/protein deacetylase inhibitor therapy for enhancement of Foxp3+ T-regulatory cell function posttransplantation

Histone/protein deacetylase inhibitor therapy for enhancement of Foxp3+ T-regulatory cell function posttransplantation

Mechanistic Insights into the Binding of Class IIa HDAC Inhibitors toward Spinocerebellar Ataxia Type-2: A 3D-QSAR and Pharmacophore Modeling Approach

Strategies for the Discovery of Target-Specific or Isoform-Selective Modulators

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