Journal ArticleDOI
Quantitative structure–activity relationship analysis and virtual screening studies for identifying HDAC2 inhibitors from known HDAC bioactive chemical libraries
Hai Pham-The,Gerardo M. Casañola-Martin,Karel Diéguez-Santana,Nam Nguyen-Hai,N T Ngoc,L Vu-Duc,Huong Le-Thi-Thu +6 more
TLDR
This study illustrates the power of ML-based QSAR approaches for the screening and discovery of potent, isoform-selective HDACIs.Abstract:
Histone deacetylases (HDAC) are emerging as promising targets in cancer, neuronal diseases and immune disorders. Computational modelling approaches have been widely applied for the virtual screening and rational design of novel HDAC inhibitors. In this study, different machine learning (ML) techniques were applied for the development of models that accurately discriminate HDAC2 inhibitors form non-inhibitors. The obtained models showed encouraging results, with the global accuracy in the external set ranging from 0.83 to 0.90. Various aspects related to the comparison of modelling techniques, applicability domain and descriptor interpretations were discussed. Finally, consensus predictions of these models were used for screening HDAC2 inhibitors from four chemical libraries whose bioactivities against HDAC1, HDAC3, HDAC6 and HDAC8 have been known. According to the results of virtual screening assays, structures of some hits with pair-isoform-selective activity (between HDAC2 and other HDACs) were revealed. This study illustrates the power of ML-based QSAR approaches for the screening and discovery of potent, isoform-selective HDACIs.read more
Citations
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Small molecule HDAC inhibitors: Promising agents for breast cancer treatment.
TL;DR: In conclusion, HDACs have shown desirable effects on breast cancer, especially when they are used in combination with other anticancer agents, and more multicenter and randomized Phase III studies are expected to be conducted pushing promising new therapies closer to the market.
Journal ArticleDOI
Quinazoline-Based Hydroxamic Acids: Design, Synthesis, and Evaluation of Histone Deacetylase Inhibitory Effects and Cytotoxicity
Doan Thanh Hieu,Duong Tien Anh,Pham-The Hai,Le-Thi-Thu Huong,Eun Jae Park,Jeong Eun Choi,Jong Soon Kang,Phan Thi Phuong Dung,Sang-Bae Han,Nguyen Hai Nam +9 more
TL;DR: Detailed investigation on the estimation of absorption, distribution, metabolism, excretion, and toxicity (ADMET) suggested that compounds 4g, 6c, and 6g, while showing potent HDAC2 inhibitory activity and cytotoxicity, also potentially displayed ADMET characteristics desirable to be expected as promising anticancer drug candidates.
Journal ArticleDOI
Evaluation of pyrrole-2,3-dicarboxylate derivatives: Synthesis, DFT analysis, molecular docking, virtual screening and in vitro anti-hepatic cancer study
Iqbal Azad,Asif Jafri,Tahmeena Khan,Yusuf Akhter,Arshad,Firoj Hassan,Naseem Ahmad,Abdul Rahman Khan,Malik Nasibullah +8 more
TL;DR: Pyrrole-2,3-dicarboxylate derivatives synthesized in this study significantly inhibited the growth of HepG2 cells in a dose-dependent manner and may be proven to be novel therapeutic candidates to cure cancer.
Journal ArticleDOI
Conformal prediction of HDAC inhibitors.
Ulf Norinder,Ulf Norinder,J. Jesús Naveja,J. Jesús Naveja,Edgar López-López,Daniel Mucs,José L. Medina-Franco +6 more
TL;DR: This work introduces a novel approach for epigenetic quantitative structure–activity relationship (QSAR) modelling using conformal prediction and discusses the development of models for 11 sets of inhibitors of histone deacetylases, which are one of the major epigenetic target families that have been screened.
References
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Chemistry, Biology, and QSAR Studies of Substituted Biaryl Hydroxamates and Mercaptoacetamides as HDAC Inhibitors—Nanomolar‐Potency Inhibitors of Pancreatic Cancer Cell Growth
Alan P. Kozikowski,Yufeng Chen,Arsen M. Gaysin,Doris N. Savoy,Daniel D. Billadeau,Ki Hwan Kim +5 more
TL;DR: To investigate the potential for isoform selectivity in the inhibition of HDACs, a small series of 2,4′‐diaminobiphenyl ligands functionalized at the para‐amino group with an appendage containing either a hydroxamate or a mercaptoacetamide group and coupled to an amino acid residue at the ortho‐aminos group are prepared.
Journal ArticleDOI
3D-QSAR studies of HDACs inhibitors using pharmacophore-based alignment.
Yadong Chen,Huifang Li,Wanquan Tang,Chengchao Zhu,Yong-Jun Jiang,Jian-Wei Zou,Qing-Sen Yu,Qidong You +7 more
TL;DR: Comparative molecular field analysis and comparative molecular similarity indices analysis were performed on hydroxamate-based HDACs inhibitors based on phamacophore alignment and revealed important structural features of the inhibitors related to the active site ofHDACs.
Journal ArticleDOI
Benzothiazole-containing hydroxamic acids as histone deacetylase inhibitors and antitumor agents.
Dao Thi Kim Oanh,Hoang Van Hai,Sang Ho Park,Hyun-Jung Kim,Byung Woo Han,Hyung-Sook Kim,Jin-Tae Hong,Sang-Bae Han,Van Thi My Hue,Nguyen Hai Nam +9 more
TL;DR: It was found that several compounds with 6C-bridge linking benzothiazole moiety and hydroxamic functional groups showed good inhibition against HDAC3 and 4 and exhibited potent cytotoxicity against five cancer cell lines with average IC(50) values of as low as 0.81 μg/ml, almost equipotent to SAHA.
Journal ArticleDOI
QSAR Studies of PC-3 cell line inhibition activity of TSA and SAHA-like hydroxamic acids
TL;DR: Quantitative structure-activity relationships (QSAR) for a series of new trichostatin A (TSA)-like hydroxamic acids for the inhibition of cell proliferation of the PC-3 cell line have been developed using molecular descriptors from Qikprop and electronic structure calculations.
Journal ArticleDOI
Novel isatin-based hydroxamic acids as histone deacetylase inhibitors and antitumor agents.
Nguyen Hai Nam,Tran Thi Lan Huong,Do Thi Mai Dung,Phan Thi Phuong Dung,Dao Thi Kim Oanh,Do Quyen,Le Thi Thanh Thao,Sang Ho Park,Kyung Rok Kim,Byung Woo Han,Jieun Yun,Jong Soon Kang,Youngsoo Kim,Sang-Bae Han +13 more
TL;DR: Docking study performed with selected compounds 3a and 6a revealed that these compounds bound to HDAC8 with higher affinities compared to SAHA.