Quantitative structure–activity relationship analysis and virtual screening studies for identifying HDAC2 inhibitors from known HDAC bioactive chemical libraries

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.

Beyond model interpretability using LDA and decision trees for α‐amylase and α‐glucosidase inhibitor classification studies

“…On the other hand, classification or non‐linear QSAR techniques have been little explored in this field (Diéguez‐Santana et al., ; Pham‐The et al., , ). Nevertheless, discriminating active compounds from inactive ones would be, in our opinion, a better option in early screening stages.…”

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

“…Organic phase was washed with toluene (10 mL), then, it was dried using vacuum and product precipitates crystals. [20] General procedure for the synthesis of maleimides 6ac: A mixture of bromomaleic anhydride 5 (3.49 mmol) and the corresponding amine hydrochloride 4a-c (5.23 mmol) were dissolved in AcOH (5 mL). The mixture was refluxed using MW for 3h.…”

“…However, to the best of our knowledge there is not yet anything reported about structures where these groups are present. Computational techniques are applied in order to justify the HDAC inhibitors activity, using extensive databases [20] and experimental crystallographic structures to corroborate the action mechanism. If such information is not available, molecular docking results a good alternative to propose a binding mode.…”

Sàng lọc in silico, thiết kế phân tử và tổng hợp các hợp chất hóa học có tác dụng ức chế enzym histon deacetylase (HDAC)

“…Ứng dụng hai mô hình QSAR về mối quan hệ định lượng giữa cấu trúc hóa học và hoạt tính ức chế HDAC2 đã công bố [7,8], bao gồm:…”