scholarly journals Use of QSAR Global Models and Molecular Docking for Developing New Inhibitors of c-src Tyrosine Kinase

2019 ◽  
Vol 21 (1) ◽  
pp. 19 ◽  
Author(s):  
Robert Ancuceanu ◽  
Bogdan Tamba ◽  
Cristina Silvia Stoicescu ◽  
Mihaela Dinu
Keyword(s):  
Tyrosine Kinase ◽  
Kinase Inhibitors ◽  
Viral Infections ◽  
Majority Vote ◽  
Quantitative Structure Activity Relationship ◽  
Ligand Docking ◽  
Simple Majority ◽  
Src Tyrosine Kinase ◽  
Molecular Ligand ◽  
Qsar Models

A prototype of a family of at least nine members, cellular Src tyrosine kinase is a therapeutically interesting target because its inhibition might be of interest not only in a number of malignancies, but also in a diverse array of conditions, from neurodegenerative pathologies to certain viral infections. Computational methods in drug discovery are considerably cheaper than conventional methods and offer opportunities of screening very large numbers of compounds in conditions that would be simply impossible within the wet lab experimental settings. We explored the use of global quantitative structure-activity relationship (QSAR) models and molecular ligand docking in the discovery of new c-src tyrosine kinase inhibitors. Using a dataset of 1038 compounds from ChEMBL database, we developed over 350 QSAR classification models. A total of 49 models with reasonably good performance were selected and the models were assembled by stacking with a simple majority vote and used for the virtual screening of over 100,000 compounds. A total of 744 compounds were predicted by at least 50% of the QSAR models as active, 147 compounds were within the applicability domain and predicted by at least 75% of the models to be active. The latter 147 compounds were submitted to molecular ligand docking using AutoDock Vina and LeDock, and 89 were predicted to be active based on the energy of binding.

scholarly journals Use of QSAR Global Models and Molecular Docking for Developing New Inhibitors of c-Src Tyrosine Kinase

2019 ◽  
Author(s):  
Robert Ancuceanu ◽  
Bogdan Tamba ◽  
Cristina Silvia Stoicescu ◽  
Mihaela Dinu
Keyword(s):  
Molecular Docking ◽  
Tyrosine Kinase ◽  
Majority Vote ◽  
Machine Learning Algorithms ◽  
Ligand Docking ◽  
Simple Majority ◽  
Data Set ◽  
Src Tyrosine Kinase ◽  
Molecular Ligand ◽  
Qsar Models

Prototype of a family of at least nine members, c-src tyrosine kinase is a therapeutically interesting target, because its inhibition might be of interest not only in a number of malignancies, but also in a diverse array of conditions, from neurodegenerative pathologies to certain viral infections. Computational methods in drug discovery are considerably cheaper than conventional methods and offer opportunities of screening very large numbers of compounds in conditions that would be simply impossible within the wet lab experimental settings. We have explored the use of global QSAR models and molecular ligand docking in the discovery of new c-src tyrosine kinase inhibitors. Using a data set of 1038 compounds from ChEMBL and 19 blocks of molecular descriptors, we have developed over 200 QSAR classification models, based on six machine learning algorithms and 17 feature selection methods. We have selected 49 with reasonably good performance (positive predictive value and balanced accuracy higher than 70% in nested cross validation) and the models were assembled by stacking with a simple majority vote and used for the virtual screening of over the “named” ZINC data set (over 100,000 compounds). 744 compounds were predicted by at least 50% of the QSAR models as active, 147 compounds were within the applicability domain and predicted by at least 75% of the models to be active. The latter 147 compounds were submitted to molecular ligand docking using Vina and Ledock, and a number of 90 were predicted to be active based on the binding energy. External data from CHEMBL and PUBCHEM confirmed that at least 7.83% (in the case of QSAR) or 6.67% (in the case of integrated QSAR and molecular docking) of the compounds are active on the c-src target.

scholarly journals Application of a Substrate-Mediated Selection with c-Src Tyrosine Kinase to a DNA-Encoded Chemical Library

Molecules ◽  
2019 ◽  
Vol 24 (15) ◽  
pp. 2764 ◽  
Author(s):  
Dongwook Kim ◽  
Yixing Sun ◽  
Dan Xie ◽  
Kyle E. Denton ◽  
Hao Chen ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Protein Tyrosine Kinase ◽  
Kinase Inhibitors ◽  
Atp Hydrolysis ◽  
Binding Mode ◽  
Activity Levels ◽  
Lead Compound ◽  
Chemical Library ◽  
Src Tyrosine Kinase ◽  
Kinase Substrates

As aberrant activity of protein kinases is observed in many disease states, these enzymes are common targets for therapeutics and detection of activity levels. The development of non-natural protein kinase substrates offers an approach to protein substrate competitive inhibitors, a class of kinase inhibitors with promise for improved specificity. Also, kinase activity detection approaches would benefit from substrates with improved activity and specificity. Here, we apply a substrate-mediated selection to a peptidomimetic DNA-encoded chemical library for enrichment of molecules that can be phosphorylated by the protein tyrosine kinase, c-Src. Several substrates were identified and characterized for activity. A lead compound (SrcDEL10) showed both the ability to serve as a substrate and to promote ATP hydrolysis by the kinase. In inhibition assays, compounds displayed IC50′s ranging from of 8–100 µM. NMR analysis of SrcDEL10 bound to the c-Src:ATP complex was conducted to characterize the binding mode. An ester derivative of the lead compound demonstrated cellular activity with inhibition of Src-dependent signaling in cell culture. Together, the results show the potential for substrate-mediated selections of DNA-encoded libraries to discover molecules with functions other than simple protein binding and offer a new discovery method for development of synthetic tyrosine kinase substrates.

scholarly journals Molecular mechanism and functional implications of thrombin-mediated tyrosine phosphorylation of PKCδ in platelets

Blood ◽  
2005 ◽  
Vol 106 (2) ◽  
pp. 550-557 ◽  
Author(s):  
Swaminathan Murugappan ◽  
Haripriya Shankar ◽  
Surya Bhamidipati ◽  
Robert T. Dorsam ◽  
Jianguo Jin ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Phosphorylation ◽  
Molecular Mechanisms ◽  
Kinase Inhibitors ◽  
Thromboxane A2 ◽  
Human Platelets ◽  
Time Dependent ◽  
Dependent Manner ◽  
Src Tyrosine Kinase ◽  
Functional Implications

Abstract Thrombin has been known to cause tyrosine phosphorylation of protein kinase C δ (PKCδ) in platelets, but the molecular mechanisms and function of this tyrosine phosphorylation is not known. In this study, we investigated the signaling pathways used by protease-activated receptors (PARs) to cause tyrosine phosphorylation of PKCδ and the role of this event in platelet function. PKCδ was tyrosine phosphorylated by either PAR1 or PAR4 in a concentration- and time-dependent manner in human platelets. In particular, the tyrosine 311 residue was phosphorylated downstream of PAR receptors. Also the tyrosine phosphorylation of PKCδ did not occur in Gαq-deficient mouse platelets and was inhibited in the presence of a phospholipase C (PLC) inhibitor U73122 and calcium chelator BAPTA (5,5′-dimethyl-bis(o-aminophenoxy)ethane-N, N, N ′, N ′-tetraacetic acid), suggesting a role for Gαq pathways and calcium in this event. Both PAR1 and PAR4 caused a time-dependent activation of Src (pp60c-src) tyrosine kinase and Src tyrosine kinase inhibitors completely blocked the tyrosine phosphorylation of PKCδ. Inhibition of tyrosine phosphorylation or the kinase activity of PKCδ dramatically blocked PAR-mediated thromboxane A2 generation. We conclude that thrombin causes tyrosine phosphorylation of PKCδ in a calcium- and Src-family kinase–dependent manner in platelets, with functional implications in thromboxane A2 generation.

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