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Journal ArticleDOI: 10.1080/07391102.2020.1726819

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
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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Topics: Demethylase (51%)
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8 results found


Open accessJournal ArticleDOI: 10.1016/J.MEEGID.2020.104451
Deep Bhowmik1, Rajat Nandi1, Rahul Jagadeesan2, Niranjan Kumar3  +2 moreInstitutions (4)
Abstract: WHO has declared the outbreak of COVID-19 as a public health emergency of international concern The ever-growing new cases have called for an urgent emergency for specific anti-COVID-19 drugs Three structural proteins (Membrane, Envelope and Nucleocapsid protein) play an essential role in the assembly and formation of the infectious virion particles Thus, the present study was designed to identify potential drug candidates from the unique collection of 548 anti-viral compounds (natural and synthetic anti-viral), which target SARS-CoV-2 structural proteins High-end molecular docking analysis was performed to characterize the binding affinity of the selected drugs-the ligand, with the SARS-CoV-2 structural proteins, while high-level Simulation studies analyzed the stability of drug-protein interactions The present study identified rutin, a bioflavonoid and the antibiotic, doxycycline, as the most potent inhibitor of SARS-CoV-2 envelope protein Caffeic acid and ferulic acid were found to inhibit SARS-CoV-2 membrane protein while the anti-viral agent's simeprevir and grazoprevir showed a high binding affinity for nucleocapsid protein All these compounds not only showed excellent pharmacokinetic properties, absorption, metabolism, minimal toxicity and bioavailability but were also remain stabilized at the active site of proteins during the MD simulation Thus, the identified lead compounds may act as potential molecules for the development of effective drugs against SARS-CoV-2 by inhibiting the envelope formation, virion assembly and viral pathogenesis

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Topics: Virion assembly (66%), Membrane protein (55%), Docking (molecular) (54%) ... read more

40 Citations


Open accessJournal ArticleDOI: 10.1016/J.HELIYON.2021.E06515
01 Mar 2021-Heliyon
Abstract: In this study we aimed at the receipt binding domain of S protein and ACE-2 receptor as a promising drug targets against SARS-CoV-2 Flavonoids with anti-viral properties were taken as ligand for molecular docking Selected flavonoids showed extremely good pharmacokinetics properties with good absorption, solubility, metabolism, excretion,distribution, bioavailability and minimal toxicity These identified lead flavonoids may act as potential compound for the development of effective drugs and may helin controlling the rapid spread of SARS-CoV-2 by potentially inhibiting the virus entry into the host cell

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18 Citations


Journal ArticleDOI: 10.1016/J.DRUDIS.2020.09.021
Abstract: The ability of epigenetic markers to affect genome function has enabled transformative changes in drug discovery, especially in cancer and other emerging therapeutic areas. Concordant with the introduction of the term 'epi-informatics', the size of the epigenetically relevant chemical space has grown substantially and so did the number of applications of cheminformatic methods to epigenetics. Recent progress in epi-informatics has improved our understanding of the structure-epigenetic activity relationships and boosted the development of models predicting novel epigenetic agents. Herein, we review the advances in computational approaches to drug discovery of small molecules with epigenetic modulation profiles, summarize the current chemogenomics data available for epigenetic targets, and provide a perspective on the greater utility of biomedical knowledge mining as a means to advance the epigenetic drug discovery.

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Topics: Chemogenomics (58%), Cheminformatics (51%), Drug discovery (50%)

11 Citations


Journal ArticleDOI: 10.1080/07391102.2020.1739557
Deep Bhowmik1, Rahul Jagadeesan2, Praveen Rai3, Rajat Nandi1  +2 moreInstitutions (3)
Abstract: Leishmania donovani, causes leishmaniasis, a global health trouble with around 89 different countries and its population under its risk. Replication initiation events have been instrumental in regu...

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Topics: Leishmania donovani (54%), Population (52%), Replication Initiation (51%) ... read more

9 Citations


Journal ArticleDOI: 10.1080/07391102.2020.1749132
Muhammad R. Suleiman1, Hanxun Wang1, Danxia Huang1, Huibin Wang1  +5 moreInstitutions (1)
Abstract: Myeloid cell leukemia-1 (Mcl-1) protein is a family of Bcl-2 (B cell lymphoma 2) rich proteases of the most common increase threshold for genetic aberrations observed in human cancer, including lung, breast, pancreatic, cervical, and ovarian cancers as well as leukemia and lymphoma. Mcl-1 is recognized as an attractive drug target in number of diseases, including cancer. In the present study we surveyed and collected queries compounds from PDB database of Mcl-1 protein and generated pharmacophore-based models adapted to screen the drug-like compounds from FDA approved database. The 206 best lead molecules from pharmacophore-screening were further evaluated by molecular docking, molecular dynamics simulation, MM-GBSA calculation, as well as experimental validation. Two hits, ZINC00601272 and ZINC00002166, showed the best docking scores, which showed a tendency to inhibit cell viability of HL60 and K562 leukemia cells with Mcl-1 expressions. Conclusively, the present study provides structural information of Mcl-1 inhibitors for next generations of cancer therapeutics through computational and experimental validation approach.Communicated by Ramaswamy H. Sarma.

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Topics: Pharmacophore (56%), Virtual screening (55%), Docking (molecular) (54%)

2 Citations


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33 results found


Yang Shi1, Yujiang Shi1Institutions (1)
16 Dec 2005-Cell
Abstract: LSD1, a homolog of nuclear amine oxidases, functions as a histone demethylase and transcriptional co-repressor. LSD1 specifically demethylates histone H3 lysine 4, which is linked to active transcription. Lysine demethylation occurs via an oxidation reaction that generates formaldehyde. Importantly, RNAi inhibition of LSD1 causes an increase in H3 lysine 4 methylation and concomitant de-repression of target genes, suggesting that LSD1 represses transcription via histone demethylation. The results thus identify a histone demethylase conserved from S. pombe to human and reveal dynamic regulation of histone methylation by both histone methylases and demethylases.

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3,281 Citations


Journal ArticleDOI: 10.1021/BI0618621
17 Mar 2007-Biochemistry
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...

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Topics: KDM1A (58%), Tranylcypromine (57%), Monoamine oxidase (56%) ... read more

282 Citations


Journal ArticleDOI: 10.1021/ACS.JCIM.6B00088
Paola Gramatica1, Alessandro Sangion1Institutions (1)
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.

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186 Citations


Open accessJournal ArticleDOI: 10.1021/JM401002R
Yi-Chao Zheng1, Ying-Chao Duan1, Jin-Lian Ma1, Rui-Min Xu1  +12 moreInstitutions (2)
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...

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Topics: Demethylase (59%), Cell growth (53%), Cancer cell (53%)

161 Citations


Journal ArticleDOI: 10.1002/MED.21350
Yi-Chao Zheng1, Jin-Lian Ma1, Zhi-Ru Wang1, Jinfeng Li1  +6 moreInstitutions (1)
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.

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Topics: Histone H3 Lysine 4 (68%), Histone methyltransferase (67%), JARID1B (66%) ... read more

140 Citations