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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.

SUBMITTER: Xu Y

PROVIDER: S-EPMC6943670 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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

Xu Yongtao Y He Zihao Z Yang Min M Gao Yunlong Y Jin Linfeng L Wang Meiting M Zheng Yichao Y Lu Xiaoyuan X Zhang Songjie S Wang Chang C Zhao Zongya Z Zhao Junqiang J Gao Qinghe Q Duan Yingchao Y

Molecules (Basel, Switzerland) 20191206 24

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 ...[more]

PMID: 31817721

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Project description:The aurora kinase is a key enzyme that is implicated in tumor growth. Research revealed that small molecules that target aurora kinase have beneficial effects as anticancer agents. In the present study, in order to identify potential antibreast cancer agents with aurora kinase inhibitory activity, we employed QSARINS software to perform the quantitative structure-activity relationship (QSAR). The statistical values resulted from the study include R2 = 0.8902, CCCtr = 0.7580, Q2 LOO = 0.7875, Q2LMO = 0.7624, CCCcv = 0.7535, R2ext = 0.8735, and CCCext = 0.8783. Among the four generated models, the two best models encompass five important variables, including PSA, EstateVSA5, MoRSEP3, MATSp5, and RDFC24. The parameters including the atomic volume, atomic charges, and Sanderson's electronegativity played an important role in designing newer lead compounds. Based on the above data, we have designed six series of compounds including 1a-e, 2a-e, 3a-e, 4a-e, 5a-e, and 6a-e. All these compounds were subjected to molecular docking studies by using AutoDock v4.2.6 against the aurora kinase protein (1MQ4). Among the above 30 compounds, the 2-amino thiazole derivatives 1a, 2a, 3e, 4d, 5d, and 6d have excellent binding interactions with the active site of 1MQ4. Compound 1a had the highest docking score (-9.67) and hence was additionally subjected to molecular dynamic simulation investigations for 100 ns. The stable binding of compound 1a with 1MQ4 was verified by RMSD, RMSF, RoG, H-bond, molecular mechanics-generalized Born surface area (MM-GBSA), free binding energy calculations, and solvent-accessible surface area (SASA) analyses. Furthermore, newly designed compound 1a exhibited excellent ADMET properties. Based on the above findings, we propose that the designed compound 1a may be utilized as the best theoretical lead for future experimental research of selective inhibition of aurora kinase, therefore assisting in the creation of new antibreast cancer drugs.

Dataset Information

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

Publications

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

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