Data Mining Practical Machine Learning Tools and Techniques

Small molecule HDAC inhibitors: Promising agents for breast cancer treatment.

In our search for novel histone deacetylases inhibitors, we have designed and synthesized a series of novel hydroxamic acids and N-hydroxybenzamides incorporating quinazoline heterocycles (4a - 4i, 6a - 6i). Bioevaluation showed that these quinazoline-based hydroxamic acids and N-hydroxybenzamides were potently cytotoxic against three human cancer cell lines (SW620, colon; PC-3, prostate; NCI-H23, lung). In term of cytotoxicity, several compounds, e.g., 4g, 4c, 4g - 4i, 6c, and 6h, displayed from 5- up to 10-fold higher potency than SAHA (suberoylanilidehydroxamic acid, vorinostat). The compounds were also generally comparable to SAHA in inhibiting HDACs with IC50 values in sub-micromolar range. Some compounds, e.g., 4g, 6c, 6e, and 6h, were even more potent HDAC inhibitors compared to SAHA in HeLa extract assay. Docking studies demonstrated that the compounds tightly bound to HDAC2 at the active binding site with binding affinities higher than that of SAHA. 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.

Quinazoline-Based Hydroxamic Acids: Design, Synthesis, and Evaluation of Histone Deacetylase Inhibitory Effects and Cytotoxicity

Evaluation of pyrrole-2,3-dicarboxylate derivatives: Synthesis, DFT analysis, molecular docking, virtual screening and in vitro anti-hepatic cancer study

The growing interest in epigenetic probes and drug discovery, as revealed by several epigenetic drugs in clinical use or in the lineup of the drug development pipeline, is boosting the generation of screening data. In order to maximize the use of structure-activity relationships there is a clear need to develop robust and accurate models to understand the underlying structure-activity relationship. Similarly, accurate models should be able to guide the rational screening of compound libraries. Herein we introduce a novel approach for epigenetic quantitative structure-activity relationship (QSAR) modelling using conformal prediction. As a case study, we discuss the development of models for 11 sets of inhibitors of histone deacetylases (HDACs), which are one of the major epigenetic target families that have been screened. It was found that all derived models, for every HDAC endpoint and all three significance levels, are valid with respect to predictions for the external test sets as well as the internal validation of the corresponding training sets. Furthermore, the efficiencies for the predictions are above 80% for most data sets and above 90% for four data sets at different significant levels. The findings of this work encourage prospective applications of conformal prediction for other epigenetic target data sets.

Conformal prediction of HDAC inhibitors.

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.

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

N T Ngoc

Papers

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