Molecular docking, 3D-QSAR, and molecular dynamics simulations of thieno[3,2-b]pyrrole derivatives against anticancer targets of KDM1A/LSD1.
04 Mar 2021-Journal of Biomolecular Structure & Dynamics (J Biomol Struct Dyn)-Vol. 39, Iss: 4, pp 1189-1202
TL;DR: 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 simulations indicated the good predictive power and statistical reliability of this model.
Abstract: 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 per...
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Cites background from "Molecular docking, 3D-QSAR, and mol..."
...SASA ensures the contribution of hydrophobic interactions of the nonpolar amino to the conformation stability of proteins in the solvent environment (Zhang et al., 2020; Bhowmik et al., 2020; Rocco et al., 2008; Kumar et al., 2018)....
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...SASA ensures the contribution of hydrophobic interactions of the nonpolar amino to the conformation stability of proteins in the solvent environment [103-106]....
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References
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TL;DR: In this paper, the authors identify a histone demethylase conserved from S. pombe to human and reveal dynamic regulation of histone methylation by both histonemethylases and demethylases.
3,281 citations
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TL;DR: It is shown that 2-PCPA is a time-dependent, mechanism-based irreversible inhibitor of LSD1 with a KI of 242 microM and a kinact of 0.0106 s-1, which will provide a foundation for the design of cyclopropylamine-based inhibitors that are selective for LSD1 to probe its role in vivo.
Abstract: The catalytic domain of the flavin-dependent human histone demethylase lysine-specific demethylase 1 (LSD1) belongs to the family of amine oxidases including polyamine oxidase and monoamine oxidase (MAO). We previously assessed monoamine oxidase inhibitors (MAOIs) for their ability to inhibit the reaction catalyzed by LSD1 [Lee, M. G., et al. (2006) Chem. Biol. 13, 563−567], demonstrating that trans-2-phenylcyclopropylamine (2-PCPA, tranylcypromine, Parnate) was the most potent with respect to LSD1. Here we show that 2-PCPA is a time-dependent, mechanism-based irreversible inhibitor of LSD1 with a KI of 242 μM and a kinact of 0.0106 s-1. 2-PCPA shows limited selectivity for human MAOs versus LSD1, with kinact/KI values only 16-fold and 2.4-fold higher for MAO B and MAO A, respectively. Profiles of LSD1 activity and inactivation by 2-PCPA as a function of pH are consistent with a mechanism of inactivation dependent upon enzyme catalysis. Mass spectrometry supports a role for FAD as the site of covalent mod...
307 citations
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TL;DR: This editorial summarizes the history of parameter development for the external QSAR model validation and suggests, once again, the concurrent use of several different metrics to assess the real predictive capability ofQSAR models.
Abstract: In the last years, external validation of QSAR models was the subject of intensive debate in the scientific literature. Different groups have proposed different metrics to find “the best” parameter to characterize the external predictivity of a QSAR model. This editorial summarizes the history of parameter development for the external QSAR model validation and suggests, once again, the concurrent use of several different metrics to assess the real predictive capability of QSAR models.
261 citations
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TL;DR: Five series of 1,2,3-triazole-dithiocarbamate hybrids were designed and synthesized and screened their inhibitory activity toward LSD1 and it was found that some of these compounds exhibited the most specific and robust inhibition of LSD1.
Abstract: Lysine specific demethylase 1 (LSD1), the first identified histone demethylase, plays an important role in epigenetic regulation of gene activation and repression. The up-regulated LSD1’s expression has been reported in several malignant tumors. In the current study, we designed and synthesized five series of 1,2,3-triazole–dithiocarbamate hybrids and screened their inhibitory activity toward LSD1. We found that some of these compounds, especially compound 26, exhibited the most specific and robust inhibition of LSD1. Interestingly, compound 26 also showed potent and selective cytotoxicity against LSD1 overexpressing gastric cancer cell lines MGC-803 and HGC-27, as well as marked inhibition of cell migration and invasion, compared to 2-PCPA. Furthermore, compound 26 effectively reduced the tumor growth bared by human gastric cancer cells in vivo with no signs of adverse side effects. These findings suggested that compound 26 deserves further investigation as a lead compound in the treatment of LSD1 overex...
195 citations
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TL;DR: A review of recent studies about LSD1 focuses on the basic physiological function of LSD1 and its involved mechanisms in pathophysiologic conditions, as well as the development of LSD 1 inhibitors as potential anticancer therapeutic agents.
Abstract: Histone lysine-specific demethylase 1 (LSD1) is the first discovered and reported histone demethylase by Dr. Shi Yang's group in 2004. It is classified as a member of amine oxidase superfamily, the common feature of which is using the flavin adenine dinucleotide (FAD) as its cofactor. Since it is located in cell nucleus and acts as a histone methylation eraser, LSD1 specifically removes mono- or dimethylated histone H3 lysine 4 (H3K4) and H3 lysine 9 (H3K9) through formaldehyde-generating oxidation. It has been indicated that LSD1 and its downstream targets are involved in a wide range of biological courses, including embryonic development and tumor-cell growth and metastasis. LSD1 has been reported to be overexpressed in variety of tumors. Inactivating LSD1 or downregulating its expression inhibits cancer-cell development. LSD1 targeting inhibitors may represent a new insight in anticancer drug discovery. This review summarizes recent studies about LSD1 and mainly focuses on the basic physiological function of LSD1 and its involved mechanisms in pathophysiologic conditions, as well as the development of LSD1 inhibitors as potential anticancer therapeutic agents.
177 citations