Browse
Submit Data
Databases
API
Help

Dataset Information

29 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Identification of potent catalytic inhibitors of human DNA topoisomerase II by structure-based virtual screening.

ABSTRACT: Human DNA topoisomerase II (Top2) is a promising target for cancer treatment. To overcome the limitations of known Top2 inhibitors, novel Top2 catalytic inhibitors with new scaffolds were identified by structure-based virtual screening. In particular, compound 8 showed good in vitro antiproliferative activity with a broad spectrum. Top2-mediated cleavage assay and molecular modeling rationalized the mode of action. The new Top2 inhibitors are considered as good starting points for further hit-to-lead optimization in anticancer drug discovery.

SUBMITTER: Dong G

PROVIDER: S-EPMC6071756 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Identification of potent catalytic inhibitors of human DNA topoisomerase II by structure-based virtual screening.

Dong Guoqiang G Wu Ying Y Sun Ying Y Liu Na N Wu Shanchao S Zhang Wannian W Sheng Chunquan C

MedChemComm 20180524 7

Human DNA topoisomerase II (Top2) is a promising target for cancer treatment. To overcome the limitations of known Top2 inhibitors, novel Top2 catalytic inhibitors with new scaffolds were identified by structure-based virtual screening. In particular, compound <b>8</b> showed good <i>in vitro</i> antiproliferative activity with a broad spectrum. Top2-mediated cleavage assay and molecular modeling rationalized the mode of action. The new Top2 inhibitors are considered as good starting points for ...[more]

PMID: 30109001

Similar Datasets

Novel DNA topoisomerase IIα inhibitors from combined ligand- and structure-based virtual screening.

Project description:DNA topoisomerases are enzymes responsible for the relaxation of DNA torsional strain, as well as for the untangling of DNA duplexes after replication, and are important cancer drug targets. One class of topoisomerase inhibitors, "poisons", binds to the transient enzyme-DNA complex which occurs during the mechanism of action, and inhibits the religation of DNA. This ultimately leads to the accumulation of DNA double strand breaks and cell death. Different types of topoisomerases occur in human cells and several poisons of topoisomerase I and II are widely used clinically. However, their use is compromised by a variety of side effects. Recent studies confirm that the inhibition of the α-isoform of topoisomerase II is responsible for the cytotoxic effect, whereas the inhibition of the β-isoform leads to development of adverse drug reactions. Thus, the discovery of agents selective for topoisomerase IIα is an important strategy for the development of topoisomerase II poisons with improved clinical profiles. Here, we present a computer-aided drug design study leading to the identification of structurally novel topoisomerase IIα poisons. The study combines ligand- and structure-based drug design methods including pharmacophore models, homology modelling, docking, and virtual screening of the National Cancer Institute compound database. From the 8 compounds identified from the computational work, 6 were tested for their capacity to poison topoisomerase II in vitro: 4 showed selective inhibitory activity for the α- over the β-isoform and 3 of these exhibited cytotoxic activity. Thus, our study confirms the applicability of computer-aided methods for the discovery of novel topoisomerase II poisons, and presents compounds which could be investigated further as selective topoisomerase IIα inhibitors.

| S-EPMC4260913 | biostudies-literature

Identification of Potent and Selective Acetylcholinesterase/Butyrylcholinesterase Inhibitors by Virtual Screening.

Project description:Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) play important roles in human neurodegenerative disorders such as Alzheimer's disease. In this study, machine learning methods were applied to develop quantitative structure-activity relationship models for the prediction of novel AChE and BChE inhibitors based on data from quantitative high-throughput screening assays. The models were used to virtually screen an in-house collection of ∼360K compounds. The optimal models achieved good performance with area under the receiver operating characteristic curve values ranging from 0.83 ± 0.03 to 0.87 ± 0.01 for the prediction of AChE/BChE inhibition activity and selectivity. Experimental validation showed that the best-performing models increased the assay hit rate by several folds. We identified 88 novel AChE and 126 novel BChE inhibitors, 25% (AChE) and 53% (BChE) of which showed potent inhibitory effects (IC50 < 5 μM). In addition, structure-activity relationship analysis of the BChE inhibitors revealed scaffolds for chemistry design and optimization. In conclusion, machine learning models were shown to efficiently identify potent and selective inhibitors against AChE and BChE and novel structural series for further design and development of potential therapeutics against neurodegenerative disorders.

| S-EPMC10688023 | biostudies-literature

Virtual Screening and Biological Activity Evaluation of New Potent Inhibitors Targeting Hexokinase-II.

Project description:Hexokinase-II (HK-II), the rate-limiting step enzyme in the glycolysis pathway, expresses high levels of cancer cells compared with normal cells. Due to its pivotal role in the different aspects of cancer physiology including cellular proliferation, metastasis, and apoptosis, HK-II provides a new therapeutic target for cancer therapy. The structure-based virtual screening targeting HK-II was used to hit identifications from small molecule databases, and the select compounds were further evaluated in biological assays. Forty-seven compounds with the lowest binding energies were identified as potential HK-II inhibitors. Among them, nine compounds displayed the highest cytotoxicity to three different cancer cells. Based on the mechanism study, compounds 4244-3659 and K611-0094 showed an obvious inhibitory effect on the HK-II enzyme. This study identified two potential inhibitors of HK-II and can be helpful for developing potential drugs targeting HK-II in tumor therapy.

| S-EPMC9658052 | biostudies-literature

Identification of potent HDAC 2 inhibitors using E-pharmacophore modelling, structure-based virtual screening and molecular dynamic simulation.

Project description:Histone deacetylase 2 (HDAC 2) of class I HDACs plays a major role in embryonic and neural developments. However, HDAC 2 overexpression triggers cell proliferation by diverse mechanisms in cancer. Over the decades, many pan and class-specific inhibitors of HDAC were discovered. Limitations such as toxicity and differential cell localization of each isoform led researchers to hypothesize that isoform selective inhibitors may be relevant to bring about desired effects. In this study, we have employed the PHASE module to develop an e-pharmacophore model and virtually screened four focused libraries of around 300,000 compounds to identify isoform selective HDAC 2 inhibitors. The compounds with phase fitness score greater than or equal to 2.4 were subjected to structure-based virtual screening with HDAC 2. Ten molecules with docking score greater than -12 kcal/mol were chosen for selectivity study, QikProp module (ADME prediction) and dG/bind energy identification. Compound 1A with the best dock score of -13.3 kcal/mol and compound 1I with highest free binding energy, -70.93 kcal/mol, were selected for molecular dynamic simulation studies (40 ns simulation). The results indicated that compound 1I may be a potent and selective HDAC 2 inhibitor. Further, in vitro and in vivo studies are necessary to validate the potency of selected lead molecule and its derivatives.

| S-EPMC9007783 | biostudies-literature

Catalytic inhibitors of DNA topoisomerase II suppress the androgen receptor signaling and prostate cancer progression.

Project description:Although the new generation of androgen receptor (AR) antagonists like enzalutamide (ENZ) prolong survival of metastatic castration-resistant prostate cancer (CRPC), AR-driven tumors eventually recur indicating that additional therapies are required to fully block AR function. Since DNA topoisomerase II (Topo II) was demonstrated to be essential for AR to initiate gene transcription, this study tested whether catalytic inhibitors of Topo II can block AR signaling and suppress ENZ-resistant CRPC growth. Using multiple prostate cancer cell lines, we showed that catalytic Topo II inhibitors, ICRF187 and ICRF193 inhibited transcription activities of the wild-type AR, mutant ARs (F876L and W741C) and the AR-V7 splice variant. ICRF187 and ICRF193 decreased AR recruitment to target promoters and reduced AR nuclear localization. Both ICRF187 and ICRF193 also inhibited cell proliferation and delayed cell cycling at the G2/M phase. ICRF187 inhibited tumor growth of castration-resistant LNCaP and 22RV1 xenografts as well as ENZ-resistant MR49F xenografts. We conclude that catalytic Topo II inhibitors can block AR signaling and inhibit tumor growth of CRPC xenografts, identifying a potential co-targeting approach using these inhibitors in combination with AR pathway inhibitors in CRPC.

| S-EPMC4653019 | biostudies-literature

Identification of novel potent human testis-specific and bromodomain-containing protein (BRDT) inhibitors using crystal structure-based virtual screening.

Project description:Human testis-specific and bromodomain-containing protein (hBRDT) is essential for chromatin remodeling during spermatogenesis and is therefore an attractive target for the discovery of male contraceptive drugs. In this study, pharmacophore modeling was carried out based on the crystal structure of hBRDT in complex with the inhibitor, JQ1. The established pharmacophore model was used as a 3D search query to identify potent hBRDT inhibitors from an in-house chemical database. A molecular docking analysis was carried out to filter the obtained hit compounds. A total of 125 compounds was finally selected based on the ranking order and visual examination. These compounds were further evaluated by a protein-based in vitro assay. Four compounds with new chemical scaffolds were identified to be hBRDT inhibitors. The most active of these compounds, T480, had a half maximal inhibitory concentration (IC50) of 9.02 µM. The detailed analysis of the binding mode of compound T480 provides important information for the further development of novel BRDT inhibitors.

| S-EPMC4899012 | biostudies-literature

Discovery of New Catalytic Topoisomerase II Inhibitors for Anticancer Therapeutics.

Project description:Poison inhibitors of DNA topoisomerase II (TOP2) are clinically used drugs that cause cancer cell death by inducing DNA damage, which mechanism of action is also associated with serious side effects such as secondary malignancy and cardiotoxicity. In contrast, TOP2 catalytic inhibitors induce limited DNA damage, have low cytotoxicity, and are effective in suppressing cancer cell proliferation. They have been sought after to be prospective anticancer therapies. Herein the discovery of new TOP2 catalytic inhibitors is described. A new druggable pocket of TOP2 protein at its DNA binding domain was used as a docking site to virtually screen ~6 million molecules from the ZINC15 library. The lead compound, T60, was characterized to be a catalytic TOP2 inhibitor that binds TOP2 protein and disrupts TOP2 from interacting with DNA, resulting in no DNA cleavage. It has low cytotoxicity, but strongly inhibits cancer cell proliferation and xenograft growth. T60 also inhibits androgen receptor activity and prostate cancer cell growth. These results indicate that T60 is a promising candidate compound that can be further developed into new anticancer drugs.

| S-EPMC7883873 | biostudies-literature

Discovery of DNA Topoisomerase I Inhibitors with Low-Cytotoxicity Based on Virtual Screening from Natural Products.

Project description:Currently, DNA topoisomerase I (Topo I) inhibitors constitute a family of antitumor agents with demonstrated clinical effects on human malignancies. However, the clinical uses of these agents have been greatly limited due to their severe toxic effects. Therefore, it is urgent to find and develop novel low toxic Topo I inhibitors. In recent years, during our ongoing research on natural antitumor products, a collection of low cytotoxic or non-cytotoxic compounds with various structures were identified from marine invertebrates, plants, and their symbiotic microorganisms. In the present study, new Topo I inhibitors were discovered from low cytotoxic and non-cytotoxic natural products by virtual screening with docking simulations in combination with bioassay test. In total, eight potent Topo I inhibitors were found from 138 low cytotoxic or non-cytotoxic compounds from coral-derived fungi and plants. All of these Topo I inhibitors demonstrated activities against Topo I-mediated relaxation of supercoiled DNA at the concentrations of 5-100 µM. Notably, the flavonoids showed higher Topo I inhibitory activities than other compounds. These newly discovered Topo I inhibitors exhibited structurally diverse and could be considered as a good starting point for the development of new antitumor lead compounds.

| S-EPMC5532659 | biostudies-literature

Cadmium is a catalytic inhibitor of DNA topoisomerase II.

Project description:Cadmium (Cd(2+)) is a highly toxic and carcinogenic metal that is an environmental and occupational hazard. DNA topoisomerase II is an essential nuclear enzyme and its inhibition can result in the formation of genotoxic and recombinogenic DNA double strand breaks. In this study we showed that cadmium chloride strongly inhibited the DNA decatenation activity of human topoisomerase II? in the low micromolar concentration range and that its inhibitory effects were reduced by glutathione. Because the activity of topoisomerase II is strongly inhibited by thiol-reactive compounds this result suggested that cadmium may be binding to critical topoisomerase II cysteine thiols. Cadmium, however, did not stabilize DNA-topoisomerase II covalent complexes, as measured by the lack of formation of DNA double strand breaks. Hence, it is not likely to be a topoisomerase II poison. Consistent with the idea that cadmium cytotoxicity may be modulated by glutathione levels, buthionine sulfoximine pretreatment to decrease glutathione levels resulted in a greatly increased cadmium-induced cytotoxicity in K562 cells. The results of this study suggest that cadmium may exert some of its cell growth inhibitory, and possibly its toxicity and carcinogenicity, by inhibiting topoisomerase II? through reaction with critical cysteine thiols.

| S-EPMC3091975 | biostudies-literature

Identification of Mycobacterium tuberculosis BioA inhibitors by using structure-based virtual screening.

Project description:Background7,8-Diaminopelargonic acid synthase (BioA), an enzyme of biotin biosynthesis pathway, is a well-known promising target for anti-tubercular drug development.MethodsIn this study, structure-based virtual screening was employed against the active site of BioA to identify new chemical entities for BioA inhibition and top ranking compounds were evaluated for their ability to inhibit BioA enzymatic activity.ResultsSeven compounds inhibited BioA enzymatic activity by greater than 60% at 100 ?g/mL with most potent compounds being A36, A35 and A65, displaying IC50 values of 10.48 ?g/mL (28.94 ?M), 33.36 ?g/mL (88.16 ?M) and 39.17 ?g/mL (114.42 ?M), respectively. Compounds A65 and A35 inhibited Mycobacterium tuberculosis (M. tuberculosis) growth with MIC90 of 20 ?g/mL and 80 ?g/mL, respectively, whereas compound A36 exhibited relatively weak inhibition of M. tuberculosis growth (83% inhibition at 200 ?g/mL). Compound A65 emerged as the most potent compound identified in our study that inhibited BioA enzymatic activity and growth of the pathogen and possessed drug-like properties.ConclusionOur study has identified a few hit molecules against M. tuberculosis BioA that can act as potential candidates for further development of potent anti-tubercular therapeutic agents.

| S-EPMC5935190 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data