1,721,004 research outputs found
Docking, 3D-QSAR studies and in silicoADME prediction on c-Src tyrosine kinase inhibitors
No full textDocking simulations and three-dimensional quantitative structure-activity relationship (3D-QSAR) analysis were performed on a wide set of c-Src inhibitors. The study was conducted using a structure-based alignment and by applying the GRID/GOLPE approach. The present 3D-QSAR investigation proved to be of good statistical value, displaying r(2), q(2) and cross-validation SDEP values of 0.94, 0.84 and 0.42, respectively. Moreover, such a model also proved to be capable of predicting the activities of an external test set of compounds. The availability of the 3D structure of the target made possible the interpretation of steric and electrostatic maps within the binding site environment and provided useful insight into the structural requirements for inhibitory activity against c-Src. Two regions whose occupation by hydrophobic portions of ligands would favourably affect the activity were clearly identified. Moreover, hydrogen bond interactions involving residues Met343, Asp406 and Ser347 emerged as playing a key role in determining the affinity of the active inhibitors toward c-Src. Furthermore, the inhibitors bearing a basic nitrogen provided enhanced potency through protonation and salt bridge formation with Asp350. A preliminary pharmacokinetic profile of the molecules under analysis was also drawn on the basis of Volsurf predictions
Targets Looking for Drugs: A Multistep Computational Protocol for the Development of Structure-Based Pharmacophores and Their Applications for Hit Discovery
No full textPharmacophoresthree-dimensional (3D) arrangements of essential features enabling a molecule to exert a particular biological effectconstitute a very useful tool in drug design both in hit discovery and hit-to-lead optimization process. Two basic approaches for pharmacophoric model generation can be used by chemists, depending on the availability or not of the target 3D structure. In view of the rapidly growing number of protein structures that are now available, receptor-based pharmacophore generation methods are becoming more and more used. Since most of them require the knowledge of the 3D structure of the ligand-target complex, they cannot be applied when no compounds targeting the binding site of interest are known. Here, a GRID-based procedure for the generation of receptor-based pharmacophores starting from the knowledge of the sole protein structure is described and successfully applied to address three different tasks in the field of medicinal chemistry
Bcr-Abl tyrosine kinase inhibitors: A patent review
No full textBreakpoint cluster region Abelson (Bcr-Abl) tyrosine kinase (TK) is a constitutively activated cytoplasmic TK and is the underlying cause of chronic myeloid leukemia (CML). To date, imatinib represents the frontline treatment for CML therapy. The development of resistance has prompted the search for novel Bcr-Abl inhibitors. Areas covered: This review presents a short overview of drugs already approved for CML therapy and of the compds. that are in clin. trials. The body of the article deals with Bcr-Abl inhibitors patented since 2008, focusing on their chem. features. Expert opinion: The search for Bcr-Abl inhibitors is very active. We believe that a no. of patented compds. could enter clin. trials and some could be approved for CML therapy in the next few years. Overall, Bcr-Abl inhibitors constitute a very appealing research field that can be expected to expand further
Protein-protein interactions and human cellular cofactors as new targets for HIV therapy
No full textTwo novel approaches for the development of new drugs against AIDS are summarized each leading to the achievement of important discoveries in anti-HIV therapy. Despite the success of HAART in reducing mortality, resistant strains continue to emerge in the clinic, underscoring the importance of developing next-generation drugs. Protein protein interactions and human cellular cofactors represent the new targets of tomorrow in HIV research. The most relevant results obtained in the last few years by the two new strategies are described herein
Preparation of 4-amino-substituted pyrazolo[3,4-d]pyrimidine and pyrrolo[2,3-d]pyrimidine derivative as the Src family kinases
No full textThe present invention refers to 4-amino-substituted pyrazolo[3,4-d]pyrimidine and pyrrolo[2,3-d]pyrimidine derivs. of formula I able to target the Src family kinases (SFKs) such as Src, Fyn and Hck tyrosine kinases as well as Abl tyrosine kinase and uses and method of prepn. thereof, wherein Z = CH or N; R2 = alkyl; Y = NH, O or S; X = CH or N; W = NH, NCH3 or S; n = 0-4; m = 0-1; R3 = H or aralkyl; R4 = substituted Ph. In particular, the compds. of the invention are for use in the treatment and/or prevention of cancer, such as neuroblastoma (NB) or glioblastoma multiform (GBM) or for use in the treatment and/or prevention of neurodegenerative diseases such as taupathies. Thus, e.g., II was prepd. and showed EC50 value of 0.20 μM against c-Src and 0.15 μM against Abl in enzymic activity assay
COMPOUNDS AND USES THEREOF
No full textThe present invention refers to 4-amino-substituted pyrazolo[3,4-d]pyrimidine and
pyrrolo[2,3-d]pyrimidine derivatives of formula I and IV able to target the Src family
kinases (SFKs) such as Src, Fyn and Hck tyrosine kinases as well as Abl tyrosine
kinase and uses and method of preparation thereof. In particular, the compounds of the
invention are for use in the treatment and/or prevention of cancer, such as
neuroblastoma (NB) or glioblastoma multiforme (GBM) or for use in the treatment
and/or prevention of neurodegenerative diseases such as taupathie
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Computational studies of the interaction between the HIV - 1 integrase tetramer and the cofactor LEDGF/p75: insights from molecular dynamics simulations and the Informational spectrum method
No full textA crystal structure of the integrase binding domain (IBD) of the lens epithelium-derived growth factor (LEDGF/p75) in complex with the dimer of the HIV-1 integrase (IN) catalytic core domain (CCD) provides useful information that might help in the understanding of essential protein-protein contacts in HIV-1. However, mutagenic studies indicated that interactions between the full-length proteins were more extensive than the contacts observed in the co-crystal structure of the isolated domains. On the other hand, the biochemical characterization of the interaction between full-length IN and LEDGF/p75 has recently proved that LEDGF/p75 promotes IN tetramerization with two LEDGF/p75 IBD molecules bound to the IN tetramer. This experimental evidence suggests that to obtain a complete structural description of the interactions between the two proteins, the full-length tetrameric structure of IN should be considered. Our aim was to obtain a detailed picture of HIV-1 IN interactions with cellular co-factors that was of general interest, particularly for the development of small molecule IN inhibitors, which mimic the IBD of LEDGF/p75. To this end, we performed bioinformatics analyses to identify protein sequence domains involved in long-range recognition. Subsequently, we applied molecular dynamics techniques to investigate the detailed interactions between the complete tetrameric form of IN and two molecules of the IBD of LEDGF/p75. Our dynamic picture is in agreement with experimental data and, thereby, provides new details of the IN-LEDGF/p75 interaction
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