Amide Analogues of TSA: Synthesis, Binding Mode Analysis and HDAC Inhibition.

Ommeslaeghe, K Van; Elaut, Greetje; Brecx, Valerie; Papeleu, Peggy; Iterbeke, Koen; Geerlings, Pau̧l; Tourwé, Dirk; Rogiers, Vera

doi:10.1002/chin.200336181

Cited by 7 publications

(9 citation statements)

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“…15,19,20,21,22 However, it is still unclear why some series of similar inhibitors display large differences in binding affinity. 23 This may be due to the fact that, except for the chelation of the catalytic zinc ion by the hydroxamic acid, it is difficult to identify common specific interactions between the enzyme and its inhibitors. For example, in the X-ray structures of TSA (1) and SAHA (2) in complex with HDLP, 24 little evidence for polar interactions can be found, except for the chelation of the zinc atom by the hydroxamic acid.…”

Section: Introductionmentioning

confidence: 99%

Ab initio study of the binding of Trichostatin A (TSA) in the active site of Histone Deacetylase Like Protein (HDLP)

et al. 2003

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Histone deacetylase (HDAC) inhibitors have recently attracted considerable interest because of their therapeutic potential for the treatment of cell proliferative diseases. An X-ray structure of a very potent inhibitor, Trichostatin A (TSA), bound to HDLP (an HDAC analogue isolated from Aquifex aeolicus), is available. From this structure, an active site model (322 atoms), relevant for the binding of TSA and structural analogues, has been derived, and TSA has been minimized in this active site at HF 3-21G* level. The resulting conformation is in excellent accordance with the X-ray structure, and indicates a deprotonation of the hydroxamic acid in TSA by His 131. Also, a water molecule was minimized in the active site. In addition to a similar deprotonation, in accordance with a possible catalytic mechanism of HDAC as proposed by Finnin et al. (M. S. Finnin, J. R. Donigian, A. Cohen, V. M. Richon, R. A. Rifkind and P. A. Marks, Nature, 1999, 401, 188-193), a displacement of the resulting OH- ion in the active site was observed. Based on these results, the difference in energy of binding between TSA and water was calculated. The resulting value is realistic in respect to experimental binding affinities. Furthermore, the mechanism of action of the His 131-Asp 166 charge relay system was investigated. Although the Asp residue in this motif is known to substantially increase the basicity of the His residue, no proton transfer from His 131 to Asp 166 was observed on binding of TSA or water. However, in the empty protonated active site, this proton transfer does occur.

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Section: Introductionmentioning

confidence: 99%

Ab initio study of the binding of Trichostatin A (TSA) in the active site of Histone Deacetylase Like Protein (HDLP)

et al. 2003

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“…Van Ommeslaeghe et al 78 reported potent amide type HDACIs and molecular modeling confirms the flexibility of the linker chain of compound 23, which is important for the orientation of the dimethyl-amino-benzoyl group in the enzyme.…”

Section: (22)mentioning

confidence: 89%

Histone Deacetylase Inhibitors: A Prospect in Drug Discovery

Yadav¹,

Mishra²,

Yadav³

2019

tjps

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Kanser tedavisi tüm toplum için büyük bir kışkırtıcıdır ve ilaç keşfi alanında bir araştırma hattını izlemektedir. Bu nedenle, işlemeyen ilaç hedeflerini iyileştirme yeterliliğine sahip, tıbbi aktif bir ajan keşfetmek için hayati bir gereklilik vardır. Artan pragmatik kanıtlar, histon deasetilazların (HDAC) kanserin ilerleme aşamasında deasetilasyonu arttırarak ve malignite değişikliklerini tetikleyerek kapana kısıldığını ifade etmektedir. HDAC inhibitörleri, ilaç keşfi bağlamında terapötik bir hedef olarak HDAC biyolojisiyle ilgili kimyasal varlığı araştırmak için, çığır açıcı iskele ve ulaşılabilir bir anahtar sağlarlar. HDAC inhibitörünün gen ekpresyonu yoluyla, kanserli hücrelere sitotoksisiteyi ihtiyatlı bir şekilde aktarmak için anti-kanser bir madde olarak geliştirilmesi yaklaşan bir gerekliliktir. Bu derlemede HDAC enziminin temelleri, inhibitörleri ve terapötik sonuçları üzerinde durulmuştur. Anahtar kelimeler: Histon deasetilaz inhibitörleri, apopitoz, çoklu tedavi yaklaşımı, kanser Cancer is a provocative issue across the globe and treatment of uncontrolled cell growth follows a deep investigation in the field of drug discovery. Therefore, there is a crucial requirement for discovering an ingenious medicinally active agent that can amend idle drug targets. Increasing pragmatic evidence implies that histone deacetylases (HDACs) are trapped during cancer progression, which increases deacetylation and triggers changes in malignancy. They provide a groundbreaking scaffold and an attainable key for investigating chemical entity pertinent to HDAC biology as a therapeutic target in the drug discovery context. Due to gene expression, an impending requirement to prudently transfer cytotoxicity to cancerous cells, HDAC inhibitors may be developed as anticancer agents. The present review focuses on the basics of HDAC enzymes, their inhibitors, and therapeutic outcomes.

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“…A variety of studies were reported in the meantime where structure-based optimization of HDAC inhibitors was successfully guided by docking the compounds into the HDLP active site. [18][19][20][21][22][23][24][25][26][27][28] In the case of HDAC1 and HDAC6 a crystal structure of the enzyme is yet to be elucidated and in its absence, homology models of HDAC-1 and HDAC-6 complexed with hydroxamate based inhibitors were generated by several groups. [29][30][31][32][33][34][35][36][37][38][39][40] The refined models were generally checked for structural integrity using molecular dynamics simulations and various protein structure checking tools.…”

Section: Docking Studies Using X-ray Structures and Homology Modelsmentioning

confidence: 99%