Abstract
A machine learning approach has been applied to virtual screening for lysine specific demethylase 1 (LSD1) inhibitors. LSD1 is an important anti-cancer target. Machine learning models to predict activity were constructed using Morgan molecular fingerprints. The dataset, consisting of 931 molecules with LSD1 inhibition activity, was obtained from the ChEMBL database. An evaluation of several candidate algorithms on the main dataset revealed that the support vector regressor gave the best model, with a coefficient of determination () of 0.703. Virtual screening, using this model, identified five predicted potent inhibitors from the ZINC database comprising more than 300,000 molecules. The virtual screening recovered a known inhibitor, RN1, as well as four compounds where activity against LSD1 had not previously been suggested. Thus, we performed a machine-learning-enabled virtual screening of LSD1 inhibitors using only the structural information of the molecules.
Highlights
Epigenetic mechanisms are fundamental in genome-dependent biological processes.By performing an important role in regulatory effects, epigenetic mechanisms participate in gene expression and transcription coordinated by the DNA sequence [1]
The molecules in the dataset cover a considerable range of lysine specific demethylase 1 (LSD1) inhibitory activity (Figure 1), which is important for machine learning algorithms to model the quantitative structure–activity relationship well
In order to visualize the mapping between the structural features and LSD1 inhibition in two dimensions, t-distributed Stochastic Neighbour Embedding (t-SNE) was applied, due to its ability to preserve local data structures from original high dimensional space while presenting clustering information
Summary
By performing an important role in regulatory effects, epigenetic mechanisms participate in gene expression and transcription coordinated by the DNA sequence [1]. These mechanisms encompass a wide spectrum of biological activities and develop dynamic regulation in gene transcriptional modulation, genome reprogramming modification, and homeostatic maintenance [2]. 1 (LSD1) is the first histone demethylase discovered to act as a dynamic modulator in genome transcriptions of cellular processes. This regulation is achieved by LSD1 catalysing the oxidative demethylation of mono and dimethylated histone H3 at.
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