Simplified staurosporine analogs as potent JAK3 inhibitors

Behrmann

J Cellular Molecular Medi

2010

Gain-of-function mutations in the genes encoding Janus kinases have been discovered in various haematologic diseases. Jaks are composed of a FERM domain, an SH2 domain, a pseudokinase domain and a kinase domain, and a complex interplay of the Jak domains is involved in regulation of catalytic activity and association to cytokine receptors. Most activating mutations are found in the pseudokinase domain. Here we present recently discovered mutations in the context of our structural models of the respective domains. We describe two structural hotspots in the pseudokinase domain of Jak2 that seem to be associated either to myeloproliferation or to lymphoblastic leukaemia, pointing at the involvement of distinct signalling complexes in these disease settings. The different domains of Jaks are discussed as potential drug targets. We present currently available inhibitors targeting Jaks and indicate structural differences in the kinase domains of the different Jaks that may be exploited in the development of specific inhibitors. Moreover, we discuss recent chemical genetic approaches which can be applied to Jaks to better understand the role of these kinases in their biological settings and as drug targets.

Section: The Growing Family Of Atp‐competitive Nanomolar Jak Inhibitorsmentioning

confidence: 99%

Perspectives for the use of structural information and chemical genetics to develop inhibitors of Janus kinases

Behrmann

J Cellular Molecular Medi

2010

“…A dataset of 113 molecules (tutorial file 2) is obtained from the marine resources having protein kinase enzyme inhibitor activity are selected and docked against 21 kinases obtained from RCSB [9] website. The software can successfully identify potential ligands (kindly consult the tutorial file 2), in which one is considered as potential molecule for drug development [10]. …”

Section: Methodsmentioning

confidence: 99%

AUDocker LE: A GUI for virtual screening with AUTODOCK Vina

et al. 2011

BackgroundAUTODOCK Vina is an open-source program which is steadfast and authentic to perform docking simulations. Though, Auto Dock Tools can help perform docking simulations with Vina, it largely remains as a platform for docking single molecule at a time.Findings"AUDocker LE" is designed with an aim to develop a software tool as a front end graphical interface with C# language to perform docking experiments in Windows based computers. It helps users to perform automated continuous docking of large ligand databases into a set of predefined protein targets. It will also help the user to analyze the results to select promising lead molecules.ConclusionAUDocker LE provides a straight forward graphical interface which can be used in a standard personal computer with Microsoft Windows XP or Windows 7 as the operating system where Autodock Vina, Python 2.5 and .net frame work are preinstalled.

Journal of Heterocyclic Chem

“…The importance of nitrogen‐containing heterocyclic compounds for biomedical and material science applications has led to an increase in the number of synthetic methods available for the preparation of this type of heterocyclic compounds .…”

Section: Introductionmentioning

confidence: 99%

Benign Approaches for the Microwave‐assisted Synthesis of Five‐membered 1,2‐N,N‐heterocycles

Kaur

2014

The development of new strategies for the synthesis of small‐sized heterocycles has remained a highly attractive but challenging proposition. An overview of the application of microwave irradiation in the synthesis of two nitrogen atoms containing five‐membered heterocyclic compounds is presented, focusing on the developments in the last 5–10 years. This contribution covers the literature concerning the total synthesis of five‐membered 1,2‐N,N‐heterocycles.