Molecular docking, 3D-QSAR, and molecular dynamics simulations of thieno[3,2-b]pyrrole derivatives against anticancer targets of KDM1A/LSD1
| Autor: | Xiangyu Zhang, Hanxun Wang, Dongmei Zhao, Jian Wang, Jiangkun Yan, Ying Wang |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Quantitative structure–activity relationship
animal structures 030303 biophysics Quantitative Structure-Activity Relationship Antineoplastic Agents Molecular Dynamics Simulation complex mixtures Pyrrole derivatives 03 medical and health sciences Molecular dynamics Structural Biology Humans Pyrroles Molecular Biology Histone Demethylases chemistry.chemical_classification 0303 health sciences Binding Sites biology Reproducibility of Results KDM1A General Medicine Combinatorial chemistry Anticancer drug Molecular Docking Simulation Enzyme chemistry biology.protein bacteria Demethylase |
| Zdroj: | Journal of Biomolecular Structure and Dynamics. 39:1189-1202 |
| ISSN: | 1538-0254 0739-1102 |
| DOI: | 10.1080/07391102.2020.1726819 |
| Popis: | Lysine-specific demethylase 1 (LSD1) is a histone-modifying enzyme, which has been proposed as a promising target for anticancer drug development. Extensive research on LSD1 inhibitors has been performed since its discovery. In order to get more information for lead identification and optimization, we carried out a molecular modeling study on a set of 43 thieno[3,2-b]pyrrole competitive inhibitors of LSD1 using three-dimensional quantitative structure-activity relationship (3D-QSAR), molecular docking and molecular dynamics (MD) simulations. Based on the co-crystallized conformer-based alignment (CCBA) method, 3D-QSAR model of thieno[3,2-b]pyrrole derivatives as LSD1 inhibitors was established. The significant statistics (q2 = 0.595, r2 = 0.959, r2pred = 0.846) of the 3D-QSAR indicated the good predictive power and statistical reliability of this model. Based on the corresponding contour maps six LSD1 inhibitors were designed and their activities were predicted by 3D-QSAR model. Meanwhile, molecular docking was performed to simulate the probable binding modes between ligands and LSD1 protein. The molecular interactions mainly contributions to the binding affinity for LSD1 inhibitions were further supplemented by 100 ns MD simulations and binding free energy calculation. Communicated by Ramaswamy H. Sarma |
| Databáze: | OpenAIRE |
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