Therapeutic target database update 2018: enriched resource for facilitating bench-to-clinic research of targeted therapeutics

Li, Ying Hong; Yu, Chun; Li, Xiao Xu; Zhang, Peng; Tang, Jing; Yang, Qingxia; Fu, Tingting; Zhang, Xiaoyu; Cui, Xili; Tu, Gao; Zhang, Yang; Li, Shuang; Yang, Fengyuan; Sun, Qiu; Chu, Qing; Zeng, Xian; Chen, Zhe; Chen, Yu Zong; Zhu, Feng

doi:10.1093/nar/gkx1076

Cited by 462 publications

(328 citation statements)

References 63 publications

(92 reference statements)

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“…The targets with higher probability score were selected for further validation via molecular docking study (61 targets). The linkage between predicted targets with the diseases was attained via UniProt [26], Pharos [27], and Therapeutic Target Databases [28]. The results are listed in Tables 1, 2, 3, 4, 5, and 6.…”

Section: Virtual Screeningmentioning

confidence: 99%

“…The grid box was defined according to the co-crystallized ligands, but in the absence of co-crystallized ligands, the grid box was defined via picking of active site amino acids. Beside the A. nilotica's phytochemical constituents, drugs that are well known to bind with the predicted targets (selected randomly from Therapeutic Target [28] and Pharos [27] databases) and the co-crystallized ligands were used as positive controls. The compounds and the targets were input in mol2 and PDB format, respectively.…”

Section: Molecular Docking Of Phytochemical Constituents With the Prementioning

confidence: 99%

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Ellagic Acid, Kaempferol, and Quercetin from Acacia nilotica: Promising Combined Drug With Multiple Mechanisms of Action

2019

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The pharmacological activity of Acacia nilotica's phytochemical constituents was confirmed with evidence-based studies, but the determination of exact targets that they bind and the mechanism of action were not done; consequently, we aim to identify the exact targets that are responsible for the pharmacological activity via the computational methods. Furthermore, we aim to predict the pharmacokinetics (ADME) properties and the safety profile in order to identify the best drug candidates. To achieve those goals, various computational methods were used including the ligand-based virtual screening and molecular docking. Moreover, pkCSM and SwissADME web servers were used for the prediction of pharmacokinetics and safety. The total number of the investigated compounds and targets was 25 and 61, respectively. According to the results, the pharmacological activity was attributed to the interaction with essential targets. Ellagic acid, Kaempferol, and Quercetin were the best A. nilotica's phytochemical constituents that contribute to the therapeutic activities, were non-toxic as well as non-carcinogen. The administration of Ellagic acid, Kaempferol, and Quercetin as combined drug via the novel drug delivery systems will be a valuable therapeutic choice for the treatment of recent diseases attacking the public health including cancer, multidrug-resistant bacterial infections, diabetes mellitus, and chronic inflammatory systemic disease.

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Section: Virtual Screeningmentioning

confidence: 99%

Section: Molecular Docking Of Phytochemical Constituents With the Prementioning

confidence: 99%

Ellagic Acid, Kaempferol, and Quercetin from Acacia nilotica: Promising Combined Drug With Multiple Mechanisms of Action

2019

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“…There is previous evidence that medendazole has anti-leukemic properties in AML 25 and indirectly interacts with tubulins according to the Therapeutic Target Database (TTD) 37 . Therefore we chose to experimentally test it, although it does not have expressed targets at 0h.…”

Section: Identification Of Cmap Drugs For Experimental Validationmentioning

confidence: 99%

Identification of drugs for leukaemia differentiation therapy by network pharmacology

et al. 2019

Preprint

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Acute leukaemias differ from their normal haematopoietic counterparts in their inability to differentiate. This phenomenon is thought to be the result of aberrant cellular reprogramming involving transcription factors (TFs). Here we leveraged on Mogrify, a network-based algorithm, to identify TFs and their gene regulatory networks that drive differentiation of the acute promyelocytic leukaemia (APL) cell line NB4 in response to ATRA (all-trans retinoic acid). We further integrated the detected TF regulatory networks with the Connectivity Map (CMAP) repository and recovered small molecule drugs which induce similar transcriptional changes. Our method outperformed standard approaches, retrieving ATRA as the top hit. Of the other drug hits, dimaprit and mebendazole enhanced ATRA-mediated differentiation in both parental NB4 and ATRA-resistant NB4-MR2 cells. Thus, we provide proof-of-principle of our network-based computational platform for drug discovery and repositioning in leukaemia differentiation therapy, which can be extended to other dysregulated disease states.

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“…[TTD] 22 ) sourced from over 300 vendors. We screened an annotated catalog of FDA-approved drugs (updated in Feb, 2013) obtained from the ZINC 12 database 23,24 against the allosteric exosite A in caspase-7 (PDB ID: 1SHJ, chain A) and the orthosteric site (PDB ID: 1F1J, chain A) using DOCK 3.6.…”

Section: Virtual Screeningmentioning

confidence: 99%

Identification of FDA‐approved drugs as novel allosteric inhibitors of human executioner caspases

et al. 2018

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The regulation of apoptosis is a tightly coordinated process and caspases are its chief regulators. Of special importance are the executioner caspases, caspase-3/7, the activation of which irreversibly sets the cell on the path of death. Dysregulation of apoptosis, particularly an increased rate of cell death lies at the root of numerous human diseases. Although several peptide-based inhibitors targeting the homologous active site region of caspases have been developed, owing to their non-specific activity and poor pharmacological properties their use has largely been restricted. Thus, we sought to identify FDA-approved drugs that could be repurposed as novel allosteric inhibitors of caspase-3/7. In this study, we virtually screened a catalog of FDA-approved drugs targeting an allosteric pocket located at the dimerization interface of caspase-3/7. From among the top-scoring hits we short-listed 5 compounds for experimental validation. Our enzymatic assays using recombinant caspase-3 suggested that 4 out of the 5 drugs effectively inhibited caspase-3 enzymatic activity in vitro with IC values ranging ~10-55 μM. Structural analysis of the docking poses show the 4 compounds forming specific non-covalent interactions at the allosteric pocket suggesting that these molecules could disrupt the adjacently-located active site. In summary, we report the identification of 4 novel non-peptide allosteric inhibitors of caspase-3/7 from among FDA-approved drugs.

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Therapeutic target database update 2018: enriched resource for facilitating bench-to-clinic research of targeted therapeutics

Cited by 462 publications

References 63 publications

Ellagic Acid, Kaempferol, and Quercetin from Acacia nilotica: Promising Combined Drug With Multiple Mechanisms of Action

Ellagic Acid, Kaempferol, and Quercetin from Acacia nilotica: Promising Combined Drug With Multiple Mechanisms of Action

Identification of drugs for leukaemia differentiation therapy by network pharmacology

Identification of FDA‐approved drugs as novel allosteric inhibitors of human executioner caspases

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