Virtual screening and optimization of Type II inhibitors of JAK2 from a natural product library

Ma, Dik‐Lung; Chan, Daniel Shiu‐Hin; Guo, Wei; Zhong, Hai‐Jing; Yang, Hui; Leung, Lai To; Gullen, Elizabeth A.; Chiu, Pauline; Cheng, Yung‐Chi; Leung, Chung‐Hang

doi:10.1039/c4cc04498c

Cited by 43 publications

(26 citation statements)

References 25 publications

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“…[24] So, to predict the possible anticancer activity mechanism, the investigated substances were also molecularly docked to epidermal growth factor receptor kinase (EGFRK) (1m17.pdb). [21][22][23][24][25][26] Gefiti- nib (N-(3-chloro-4-fluoro-phenyl)-7-methoxy-6-(3-morpholin-4-yl-propoxy)quinazolin-4-amine) was used as a reference. [24] It was found that N-(4-fluorophenyl)- Table S2).…”

Section: Docking Studies To Epidermal Growth Factor Receptor Kinasementioning

confidence: 99%

2‐Heteroaryl‐[1,2,4]triazolo[1,5‐c]quinazoline‐5(6 H)‐thiones and Their S‐Substituted Derivatives: Synthesis, Spectroscopic Data, and Biological Activity

et al. 2015

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In the continuing search for novel, biologically effective heterocyclic agents, several methods for the synthesis of 2‐heteroaryl‐[1,2,4]triazolo[1,5‐c]quinazoline‐5(6 H)‐thiones have been developed: thiolation of oxo derivatives, [5+1] cyclocondensation of [2‐(3‐heteroaryl‐[1,2,4]triazol‐5‐yl)phenyl]amines with carbon disulfide, potassium ethyl xanthogenate, or aryl isothiocyanates, and in situ reaction of 2‐isothiocyanatobenzonitrile with hydrazides. A series of N‐R‐2‐[(2‐heteroaryl‐[1,2,4]triazole‐[1,5‐c]quinazoline‐5‐yl)thio]acetamides were obtained by aminolysis of the corresponding acetic acids and alkylation of potassium thiolates with N‐R‐2‐chloroacetamides. It was established that some potassium thiolates, 4 a–4 d, 4 h, and 4 i, had high antibacterial activity against Staphylococcus aureus with a minimum inhibitory concentration of 12.5 μg mL−1 and minimum bactericidal concentration of 25 μg mL−1, which exceeded the values for trimethoprim. In addition, {2‐[3‐(1 H‐indole‐2‐yl)‐1 H‐1,2,4‐triazol‐5‐yl]phenyl}amine 2 i was investigated in the concentration range 100–0.01 μM at 59 lines of nine cancer cell types, and showed a mean effective concentration at 3.12–7.03 μM and cytotoxic effect at 15.56–67.38 μM. The possible mechanisms of activity were predicted by molecular docking studies to S. aureus dihydrofolate reductase and epidermal growth factor receptor kinase.

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Section: Docking Studies To Epidermal Growth Factor Receptor Kinasementioning

confidence: 99%

2‐Heteroaryl‐[1,2,4]triazolo[1,5‐c]quinazoline‐5(6 H)‐thiones and Their S‐Substituted Derivatives: Synthesis, Spectroscopic Data, and Biological Activity

et al. 2015

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“…The use of in silico methodology has opened new avenues in the field of drug discovery and development, including in the design of novel chemical inhibitors by protein structural analysis 7 8 , drug library screening using quantitative structure-activity relationship (QSAR) methods 9 10 and multi-scale modelling 11 . Computational fluid dynamics (CFD) is a well known in silico approach used throughout the fields of engineering, physics and increasingly biology.…”

mentioning

confidence: 99%

Modelling the Transport of Nanoparticles under Blood Flow using an Agent-based Approach

Fullstone

Wood

Holcombe

et al. 2015

Sci Rep

114

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Blood-mediated nanoparticle delivery is a new and growing field in the development of therapeutics and diagnostics. Nanoparticle properties such as size, shape and surface chemistry can be controlled to improve their performance in biological systems. This enables modulation of immune system interactions, blood clearance profile and interaction with target cells, thereby aiding effective delivery of cargo within cells or tissues. Their ability to target and enter tissues from the blood is highly dependent on their behaviour under blood flow. Here we have produced an agent-based model of nanoparticle behaviour under blood flow in capillaries. We demonstrate that red blood cells are highly important for effective nanoparticle distribution within capillaries. Furthermore, we use this model to demonstrate how nanoparticle size can selectively target tumour tissue over normal tissue. We demonstrate that the polydispersity of nanoparticle populations is an important consideration in achieving optimal specificity and to avoid off-target effects. In future this model could be used for informing new nanoparticle design and to predict general and specific uptake properties under blood flow.

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“…Natural products are indispensable candidates in current drug discovery programs, which have inspired chemists and physicians for millennia. 1,2 However, specic action mechanisms and target locations appear to be the bottleneck for further development of natural products. Therefore, novel strategies or combined methodologies are required to decipher complex systems.…”

Section: Introductionmentioning

confidence: 99%

Discovery and verification of the potential targets from bioactive molecules by network pharmacology-based target prediction combined with high-throughput metabolomics

et al. 2017

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Virtual screening and optimization of Type II inhibitors of JAK2 from a natural product library

Cited by 43 publications

References 25 publications

2‐Heteroaryl‐[1,2,4]triazolo[1,5‐c]quinazoline‐5(6 H)‐thiones and Their S‐Substituted Derivatives: Synthesis, Spectroscopic Data, and Biological Activity

2‐Heteroaryl‐[1,2,4]triazolo[1,5‐c]quinazoline‐5(6 H)‐thiones and Their S‐Substituted Derivatives: Synthesis, Spectroscopic Data, and Biological Activity

Modelling the Transport of Nanoparticles under Blood Flow using an Agent-based Approach

Discovery and verification of the potential targets from bioactive molecules by network pharmacology-based target prediction combined with high-throughput metabolomics

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