Investigating the Binding Mode of Reversible LSD1 Inhibitors Derived from Stilbene Derivatives by 3D-QSAR, Molecular Docking, and Molecular Dynamics Simulation

Abstract

Overexpression of lysine specific demethylase 1 (LSD1) has been found in many cancers. New anticancer drugs targeting LSD1 have been designed. The research on irreversible LSD1 inhibitors has entered the clinical stage, while the research on reversible LSD1 inhibitors has progressed slowly so far. In this study, 41 stilbene derivatives were studied as reversible inhibitors by three-dimensional quantitative structure–activity relationship (3D-QSAR). Comparative molecular field analysis (CoMFA q 2 = 0.623, r 2 = 0.987, r pred 2 = 0.857) and comparative molecular similarity indices analysis (CoMSIA q 2 = 0.728, r 2 = 0.960, r pred 2 = 0.899) were used to establish the model, and the structure–activity relationship of the compounds was explained by the contour maps. The binding site was predicted by two different kinds of software, and the binding modes of the compounds were further explored. A series of key amino acids Val288, Ser289, Gly314, Thr624, Lys661 were found to play a key role in the activity of the compounds. Molecular dynamics (MD) simulations were carried out for compounds 04, 17, 21, and 35, which had different activities. The reasons for the activity differences were explained by the interaction between compounds and LSD1. The binding free energy was calculated by molecular mechanics generalized Born surface area (MM/GBSA). We hope that this research will provide valuable information for the design of new reversible LSD1 inhibitors in the future.

Design and Identification of Two Novel Resveratrol Derivatives As Potential LSD1 Inhibitors

“…Datasets & structure alignment Thirty-four reported resveratrol derivative LSD1 inhibitors [38][39][40] were collected to establish 3D-QSAR models. Their structures and biological activity data are summarized in Table 1.…”

“…From the predicted pIC 50 values of these six derivatives through the established CoMFA and CoMSIA models (Table 6), we can see that the pIC 50 values range from 5.128 to 5.742 (CoMFA) and from 4.795 to 5.836 are also prominent in these six novel inhibitors [40]. Therefore in vitro antiproliferative assay was further carried out on these compounds.…”

“…The other groups of 39 and 40 are all H atoms. The 1 H-NMR, 13 C-NMR and high-resolution MS spectra of these six newly designed compounds have been presented in our previous work [40].…”

“…Compared with the irreversible inhibitors, reversible LSD1 inhibitors have more potential advantages in phenotype and safety [27]. Among the reported reversible inhibitors, some derivatives based on the structure of resveratrol (IC LSD1 50 = 10.20 μM) have showed good specific inhibitory effects on LSD1, such as inhibitor 01 (IC 50 = 121 nM), inhibitor 02 (IC 50 = 123 nM) and inhibitor 07 (IC 50 = 283 nM) in Table 1 (the inhibitors are numbered in the order of their pIC 50 values) [38][39][40]. Moreover, 07 exhibited a reversible pattern of rapid association and slow decomposition during binding to LSD1, and its IC 50 values on human leukemia THP-1 and MOLM-13 cells (IC THP-1 50 = 5.576 μM, IC MOLM-13 50 = 8.34 μM) were both at micromolar level [39].…”

Machine-Learning-Enabled Virtual Screening for Inhibitors of Lysine-Specific Histone Demethylase 1

“…There have been several computational studies of inhibitors of LSD1, using techniques such as pharmacophore modelling, 3D-QSAR, and molecular docking. In one study [17], CoMFA [18] was used to generate a 3D-QSAR model of 41 stilbene derivatives, and this was supplemented with molecular docking and molecular dynamics simulations. A similar approach was adopted in a study of some thieno[3,2-b]pyrrole-5-carboxamide derivatives [19] and in a study of some tranylcypromine derivatives [20].…”