scholarly journals Structure-Based Design of Tetrahydroisoquinoline-Based Hydroxamic Acid Derivatives Inhibiting Human Histone Deacetylase 8

2021 ◽  
Vol 5 (1) ◽  
pp. 504-538
Author(s):  
Eugene Megnassan ◽  
◽  
Issouf Fofana ◽  
Brice Dali ◽  
Frederica Mansilla Koblavi ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Active Site ◽  
Hydroxamic Acid ◽  
Combinatorial Library ◽  
Structural Information ◽  
Qsar Model ◽  
Interaction Energies ◽  
Histone Deacetylase 8 ◽  
Hdac8 Inhibitors ◽  
Hydroxamic Acid Derivatives

We have designed new human histone deacetylase 8 (HDAC8) inhibitors using structure-based molecular design. 3D models of HDAC8–inhibitor complexes were prepared by in situ modification of the crystal structure of HDAC8 co-crystallized with the hydroxamic acid suberoylanilide (SAHA) and a training set (TS) of tetrahydroisoquinoline-based hydroxamic acid derivatives (DAHTs) with known inhibitory potencies. A QSAR model was elaborated for the TS yielding a linear correlation between the computed Gibbs free energies (GFE) of HDAC8–DAHTs complexation (∆∆Gcom) and observed half-maximal enzyme inhibitory concentrations (IC50exp). From this QSAR model a 3D-QSAR pharmacophore (PH4) was generated. Structural information derived from the 3D model and breakdown of computed HDAC8–DAHTs interaction energies up to individual active site residue contributions helped us to design new more potent HDAC8 inhibitors. We obtained a reasonable agreement ∆∆Gcom and values: (pIC50exp = – 0.0376 × ∆∆Gcom + 7.4605, R2 = 0.89). Similar agreement was established for the PH4 model (pIC50exp = 0.8769 × + 0.7854, R2 = 0.87). A comparative analysis of the contributions of active site residues guided the choice of fragments used in designing a virtual combinatorial library (VCL) of DAHT analogs. The VCL of more than 17 thousand DAHTs was screened by the PH4 and furnished 229 new DAHTs. The best-designed analog displayed predicted inhibitory potency up to 110 times higher than that of DAHT1 (IC50exp = 0.047 µM). Predicted pharmacokinetic profiles of the new analogs were compared to current per oral anticancer compounds. This computational approach, which combines molecular modelling, pharmacophore generation, analysis of HDAC8–DAHTs interaction energies and virtual screening of a combinatorial library of DAHTs resulted in a set of proposed new HDAC8 inhibitors. It can thus direct medicinal chemists in their search for new anticancer agents.

Synthesis and 4D-QSAR Studies of Alanine Hydroxamic Acid Derivatives as Aminopeptidase N Inhibitors

2019 ◽  
Vol 16 ◽  
Author(s):  
Min Gao ◽  
Qiao Li Lv ◽  
Hou Pan Zhang ◽  
Guo Gang Tu
Keyword(s):  
Biological Activity ◽  
Active Site ◽  
Hydroxamic Acid ◽  
Binding Mode ◽  
Qsar Model ◽  
Aminopeptidase N ◽  
Design Synthesis ◽  
Qsar Studies ◽  
Hydroxamic Acid Derivatives

Background: As a target for anticancer treatment, aminopeptidase N (APN) shows its overexpression on diverse malignant tumor cells and associates with cancer invasion, angiogenesis and metastasis. Objective: Design, synthesis and biological activity evaluation of alanine hydroxamic acid derivatives as APN inhibitors, and investigation the binding mode of inhibitors in the APN active site. Methods: Alanine hydroxamic acid derivatives were synthesized and evaluated for their in vitro anti-cancer activity using CCK-8 assay. Molecular docking and 4D-QSAR studies were carried out to suggest the mechanism of biological activity. Results: Compared with Bestatin, compound 9b showed the best APN inhibition activity. The putative binding mode of 9b in the APN active site was also discussed. Moreover, the robust and reliable 4D-QSAR model exhibited the following statistics: R2 = 0.9352, q2LOO = 0.8484, q2LNO =0.7920, R2Pred = 0.8739. Conclusion: Newly synthesized compounds exerted acceptable anticancer activity and further investigation on current scaffold would be beneficial.

scholarly journals Characterization of Histone Deacetylase 8 (HDAC8) Selective Inhibition Reveals Specific Active Site Structural and Functional Determinants

2018 ◽  
Vol 61 (22) ◽  
pp. 10000-10016 ◽  
Author(s):  
Martin Marek ◽  
Tajith B. Shaik ◽  
Tino Heimburg ◽  
Alokta Chakrabarti ◽  
Julien Lancelot ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Active Site ◽  
Selective Inhibition ◽  
Histone Deacetylase 8

scholarly journals Hydroxamic acid derivatives as HDAC1, HDAC6 and HDAC8 inhibitors with antiproliferative activity in cancer cell lines

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Yudibeth Sixto-López ◽  
José Antonio Gómez-Vidal ◽  
Nuria de Pedro ◽  
Martiniano Bello ◽  
Martha Cecilia Rosales-Hernández ◽  
...  
Keyword(s):  
Cell Lines ◽  
Cancer Cell ◽  
Antiproliferative Activity ◽  
Hydroxamic Acid ◽  
Cancer Cell Lines ◽  
Hdac8 Inhibitors ◽  
Hydroxamic Acid Derivatives

Design, synthesis, and evaluation of cyclic amide/imide-bearing hydroxamic acid derivatives as class-selective histone deacetylase (HDAC) inhibitors

2006 ◽  
Vol 14 (22) ◽  
pp. 7625-7651 ◽  
Author(s):  
Chihiro Shinji ◽  
Satoko Maeda ◽  
Keisuke Imai ◽  
Minoru Yoshida ◽  
Yuichi Hashimoto ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Hydroxamic Acid ◽  
Hdac Inhibitors ◽  
Design Synthesis ◽  
Cyclic Amide ◽  
Hydroxamic Acid Derivatives

scholarly journals A Novel Class of Schistosoma mansoni Histone Deacetylase 8 (HDAC8) Inhibitors Identified by Structure-Based Virtual Screening and In Vitro Testing

Molecules ◽  
2018 ◽  
Vol 23 (3) ◽  
pp. 566 ◽  
Author(s):  
Conrad Simoben ◽  
Dina Robaa ◽  
Alokta Chakrabarti ◽  
Karin Schmidtkunz ◽  
Martin Marek ◽  
...  
Keyword(s):  
Virtual Screening ◽  
Schistosoma Mansoni ◽  
Histone Deacetylase ◽  
In Vitro Testing ◽  
Histone Deacetylase 8 ◽  
Hdac8 Inhibitors

A lazy learning-based QSAR classification study for screening potential histone deacetylase 8 (HDAC8) inhibitors

2015 ◽  
Vol 26 (5) ◽  
pp. 397-420 ◽  
Author(s):  
G.P. Cao ◽  
M. Arooj ◽  
S. Thangapandian ◽  
C. Park ◽  
V. Arulalapperumal ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Lazy Learning ◽  
Histone Deacetylase 8 ◽  
Hdac8 Inhibitors

scholarly journals In silico, Synthesis and Biological Investigations of Pyrrolo[3,4-C]Pyrrole Hydroxamic Acid Derivatives as Potential Anticancer Agents

2018 ◽  
Vol 61 (4) ◽  
Author(s):  
Luis Bahena ◽  
Carlos Cervantes ◽  
Karla J Soto-Arredondo ◽  
Minerva Martínez-Alfaro ◽  
Natanael Zarco ◽  
...  
Keyword(s):  
Density Functional Theory ◽  
Active Site ◽  
Hydroxamic Acid ◽  
Density Functional ◽  
Suberoylanilide Hydroxamic Acid ◽  
Functional Theory ◽  
Reactivity Descriptors ◽  
Anti Cancer ◽  
Biological Target ◽  
Hydroxamic Acid Derivatives

Based in a general structural pharmacophore model of suberoylanilide hydroxamic acid (commercially known as Vorinostat©), we synthesized a series of new pyrrolo[3,4-c]pyrrole hydroxamic acid derivatives, <strong>9a-c</strong>, to be tested as candidates for anti-cancer drugs. The evaluation of their possible biological activity was assessed in two ways: a) computational characterization from molecular calculations and quantum reactivity descriptors and b) biological assays. Molecular docking and density functional theory calculations were performed to assess the binding properties of our newly synthesized pyrrolo[3,4-c] pyrrole hydroxamic acid derivatives, employing as the biological target the histone deacetylase isoforms available in the protein data bank. Furthermore, to characterize the effect of changing the functional groups that we varied while designing our drug model, and to improve the assessment of the binding energy, conceptual density functional theory reactivity descriptors were calculated to rationalize the capability of the new drugs to interact with the histones active site. Our findings show that the newly synthesized derivative, <strong>9c</strong>, display the best energetic coupling with the biological target and the more favorable values of the density functional theory descriptors to interact with the active site. The biological assay of the anti-cancer drug candidates was done using three different techniques: i) anti-proliferative activity on two breast cancer cell lines; ii) Histone H3 acetylation; and iii) DNA damage. Docking studies were performed on histone deacetylase enzymes. The biological function of these enzymes is the deacetylation of histones. We analyze the level of histone acetylation in two cell lines. The computational findings are in good agreement with the biological evaluation. Our main contribution is that one of our newly synthesized derivatives, <strong>9c</strong>, performs better than the commercial reference suberoylanilide hydroxamic acid.

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