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Design of Selective Inhibitors of Tyrosine Kinase 2
Abstract
Selective inhibitors of tyrosine kinase 2 (Tyk2) were searched for using database screening, de novo ligand design and computational docking in Tyk2 and seven other protein kinases. None of the structures in the National Cancer Institute database seem to inhibit Tyk2 selectively, but five of the designed structures seem promising.
... Using these computational methods, many small molecules have been developed for more than 30 targets 24 . These small molecules include the inhibitors of aldose reductase 25 , CDK4 26 , matriptase 27 , Bcl-2 28 , adenovirus protease 29 , tyrosine kinase 2 30 and synthetic agonists of cytokine receptors 31,32 . ...
... 11 Since its release, LigBuilder 1.2 has been widely used and applied successfully in a number of drug design projects. 16,18,20,21 To increase the applicability of computational de novo drug design, we have developed a new generation of this program, LigBuilder 2.0. With this version, the synthesis accessibility of designed compounds can be analyzed with the aid of an embedded chemical reaction database and a retro-synthesis analyzer. ...
We have developed a new version (2.0) of the de novo drug design program LigBuilder. With LigBuilder 2.0, the synthesis accessibility of designed compounds can be analyzed, and a cavity detection procedure is implemented to detect the positions and shapes of the binding sites on the surface of a given protein structure and to quantitatively estimate drugability. Ligands are designed to best fit the detected cavities using a set of rules for evaluation. Drug-like and privileged fragments are used to construct the ligands with the aid of internal and external absorption, distribution, metabolism, excretion, and toxicity (ADME/T) and drug-like filters.
Interaction of CD40 ligand (CD40L) with CD40 receptor is one of the most immunologically important interactions that involve in the regulation of T cell dependent B cell proliferation, differentiation and antibody production. Therefore, interfering CD40L interaction with CD40 may have important therapeutic applications. Using the three dimensional structure of CD40-CD40L complex, a small CD40L mimetic molecule, N-benzhydrylbenzamide was designed using computational techniques. This N-benzhydrylbenzamide was synthesized using Gabriel synthesis and Scotten-Baumann benzoylation reactions and characterized by FTIR and NMR spectroscopy. The FTIR spectrum of N-benzhydrylbenzamide shows the presence of various functional groups such as amide, aromatic groups and stretching vibrations for benzene derivatives. In addition, the 1H NMR spectrum of N-benzhydrylbenzamide confirmed the presence of amide and phenyl group hydrogens whereas the 13C NMR spectrum shows the presence of aromatic carbons and carbonyl group carbon. As the N-benzhydrylbenzamide structurally mimics CD40L, it can be considered as a candidate molecule for the further development of novel immunotherapeutic agent.
BTK and ITK are cytoplasmic tyrosine kinases of crucial importance for B- and T-cell development, with loss-of-function mutations causing X-linked agammaglobuinemia and susceptibility to severe, frequently lethal, Epstein-Barr virus infection, respectively. Over the last few years, considerable efforts have been made in order to develop small molecule inhibitors for these kinases to treat lymphocyte malignancies, autoimmunity or allergy/hypersensitivity. The rationale is that even if complete lack of BTK or ITK during development causes severe immunodeficiency, inactivation after birth may result in a less severe phenotype. Moreover, therapy can be transient or only partially block the activity of BTK or ITK. Furthermore, a drug-induced B-cell deficiency is treatable by gamma globulin substitution therapy. The newly developed BTK inhibitor PCI-32765, recently renamed Ibrutinib, has already entered several clinical trials for various forms of non-Hodgkin lymphoma as well as for multiple myeloma. Experimental animal studies have demonstrated highly promising treatment effects also in autoimmunity. ITK inhibitors are still under the early developmental phase, but it can be expected that such drugs will also become very useful. In this manuscript we present BTK and ITK with their signaling pathways and review the development of the corresponding inhibitors. This article is protected by copyright. All rights reserved.
BTK and ITK are cytoplasmic tyrosine kinases of crucial importance for B and T cell development, with loss-of-function mutations causing X-linked agam-maglobulinemia and susceptibility to severe, frequently lethal, Epstein–Barr virus infection, respectively. Over the last few years, considerable efforts have been made in order to develop small-molecule inhibitors for these kinases to treat lymphocyte malignancies, autoimmunity or allergy/hypersensitivity. The rationale is that even if complete lack of BTK or ITK during development causes severe immunodeficiency, inactivation after birth may result in a less severe phenotype. Moreover, therapy can be transient or only partially block the activity of BTK or ITK. Furthermore, a drug-induced B cell deficiency is treatable by gamma globulin substitution therapy. The newly developed BTK inhibitor PCI-32765, recently renamed Ibrutinib, has already entered several clinical trials for various forms of non-Hodgkin lymphoma as well as for multiple myeloma. Experimental animal studies have demonstrated highly promising treatment effects also in autoimmunity. ITK inhibitors are still under the early developmental phase, but it can be expected that such drugs will also become very useful. In this study, we present BTK and ITK with their signalling pathways and review the development of the corresponding inhibitors.
Carboxylesterases (CEs) are important enzymes that catalyze biological detoxification, hydrolysis of certain pesticides, and metabolism of many esterified drugs. The development of inhibitors for CE has many potential uses, including increasing drug lifetime and altering biodistrubution; reducing or abrogating toxicity of metabolized drugs; and reducing pest resistance to insecticides. In this review, we discuss the major classes of known mammalian CE inhibitors and describe our computational efforts to design new scaffolds for development of novel, selective inhibitors. We discuss several strategies for in silico inhibitor development, including structure docking, database searching, multidimensional quantitative structure activity analysis (QSAR), and a newly-used approach that uses QSAR combined with de novo drug design. While our research is focused on design of specific inhibitors for human intestinal carboxylesterase (hiCE), the methods described are generally applicable to inhibitors of other enzymes, including CE from other tissues and organisms.
A study on transition metal catalyzed alkyne cyclotrimerization of unsymmetrically bromo-substituted
diynes with ethynyltrimethylsilane was carried out to prepare bicyclic bromobenzene key intermediates
for the total synthesis of five potential tyrosine kinase 2 inhibitors. Two different pre-catalysts
(Cp*RuCl(cod) and [Rh(cod)2]BF4/BINAP) and different reaction conditions have been examined.
Protein-mediated interactions and enzymatic function provide the foundation upon which cellular signaling cascades control all of the activities of a cell. Post-translational modifications such as phosphorylation or ubiquitiation are well known means for modulating protein activity within the cell. These chemical modifications create new recognition motifs on proteins or shift conformational preferences such that protein catalytic and binding functions are altered in response to external stimuli. Moreover, detection of such modifications is often straightforward by conventional biochemical methods leading investigators toward mechanistic models of cell signaling involving post-translational modifications such as phosphorylation/dephosphorylation. While there is little doubt that such modifications play a significant role in transmission of information throughout the cell, there are certainly other mechanisms at work that are not as well understood at this time. Of particular interest in the context of this review is the intrinsic conformational switch afforded to a polypeptide by peptidyl prolyl cis/trans isomerization. Proline isomerization is emerging as a critical component of certain cell signaling cascades. In addition to serving as a conformational switch that enables a protein to adopt functionally distinct states, proline isomerization may serve as a recognition element for the ubiquitous peptidyl prolyl isomerases. This overview takes a close look at one particular signaling protein, the T cell specific tyrosine kinase Itk, and examines the role of proline isomerization and the peptidyl prolyl isomerase cyclophilin A in mediating Itk function following T cell receptor engagement.
Interferons and cytokines modulate gene expression via a simple, direct signaling pathway containing receptors, JAK tyrosine
kinases, and STAT transcription factors. The interferon-α pathway is a model for these cascades. Two receptors, IFNaR1 and
IFNaR2, associate exclusively in a constitutive manner with two JAK proteins, TYK2 and JAK1, respectively. Defining the molecular
interface between JAK proteins and their receptors is critical to understanding the signaling pathway and may contribute to
the development of novel therapeutics. This report defines the IFNaR1 interaction domain on TYK2. In vitro binding studies demonstrate that the amino-terminal half of TYK2, which is ∼600 amino acids long and contains JAK homology
(JH) domains 3–7, comprises the maximal binding domain for IFNaR1. A fragment containing amino acids 171–601 (JH3–6) also
binds IFNaR1, but with reduced affinity. Glutathione S-transferase-TYK2 fusion proteins approximating either the JH6 or JH3 domain affinity-precipitate IFNaR1, suggesting that
these are major sites of interaction within the larger binding domain. TYK2 amino acids 1–601 act in a dominant manner to
inhibit the transcription of an interferon-α-dependent reporter gene, presumably by displacing endogenous TYK2 from the receptor.
This same fragment inhibits interferon-α-dependent tyrosine phosphorylation of TYK2, STAT1, and STAT2.
Cytokine signaling involves the activation of the Janus kinase (JAK) family of tyrosine kinases. These enzymes are physically
associated with cytokine receptor components. Here, we sought to define the molecular basis of the interaction between Tyk2
and IFNAR1, a component of the interferon α/β receptor, by delimiting a minimal IFNAR1 binding region in the Tyk2 protein.
Using an in vitro assay system, we narrowed down the interaction domain to a region comprising the JH7 and part of the JH6 homology boxes (amino
acids 22–221). When expressed in Tyk2-negative cells, the JH7-6 region was unable to stabilize IFNAR1 protein levels, a critical
function that we previously attributed to the N region (amino acids 1–591) of Tyk2. Moreover, substitution of the JH7-JH6
domain in JAK1 with that of Tyk2 did not restore IFNAR1 level nor interferon α signaling in Tyk2-negative cells. Thus, the
major interaction surface lies within JH7-6, but additional JH regions (JH5-4-3) contribute in a specific manner to the in vivo assembly of Tyk2 and IFNAR1. Evidence is also provided of the lack of specificity of the Tyk2 kinase-like and tyrosine kinase
domains in interferon α/β receptor signaling.
Comparative modeling predicts the three-dimensional structure of a given protein sequence (target) based primarily on its alignment to one or more proteins of known structure (templates). The prediction process consists of fold assignment, target-template alignment, model building, and model evaluation. The number of protein sequences that can be modeled and the accuracy of the predictions are increasing steadily because of the growth in the number of known protein structures and because of the improvements in the modeling software. Further advances are necessary in recognizing weak sequence-structure similarities, aligning sequences with structures, modeling of rigid body shifts, distortions, loops and side chains, as well as detecting errors in a model. Despite these problems, it is currently possible to model with useful accuracy significant parts of approximately one third of all known protein sequences. The use of individual comparative models in biology is already rewarding and increasingly widespread. A major new challenge for comparative modeling is the integration of it with the torrents of data from genome sequencing projects as well as from functional and structural genomics. In particular, there is a need to develop an automated, rapid, robust, sensitive, and accurate comparative modeling pipeline applicable to whole genomes. Such large-scale modeling is likely to encourage new kinds of applications for the many resulting models, based on their large number and completeness at the level of the family, organism, or functional network.
The structure of human Janus kinase 2 (JAK2) comprising the two C-terminal domains (JH1 and JH2) was predicted by application
of homology modelling techniques. JH1 and JH2 represent the tyrosine kinase and tyrosine kinase-like domains, respectively,
and are crucial for function and regulation of the protein. A comparison between the structures of the two domains is made
and structural differences are highlighted. Prediction of the relative orientation of JH1 and JH2 was aided by a newly developed
method for the detection of correlated amino acid mutations. Analysis of the interactions between the two domains led to a
model for the regulatory effect of JH2 on JH1. The predictions are consistent with available experimental data on JAK2 or
related proteins and provide an explanation for inhibition of JH1 tyrosine kinase activity by the adjacent JH2 domain.
The goal of this study was to determine the role of the Janus tyrosine kinase (JAK)-signal transducers and activators of transcription (STAT) pathway in the late phase of ischemic preconditioning (PC). A total of 230 mice were used. At 5 min after ischemic PC (induced with six cycles of 4-min coronary occlusion/4-min reperfusion), immunoprecipitation with anti-phosphotyrosine (anti-pTyr) antibodies followed by immunoblotting with anti-JAK antibodies revealed increased tyrosine phosphorylation of JAK1 (+257 +/- 53%) and JAK2 (+238 +/- 35%), indicating rapid activation of these two kinases. Similar results were obtained by immunoblotting with anti-pTyr-JAK1 and anti-pTyr-JAK2 antibodies. Western analysis with anti-pTyr-STAT antibodies demonstrated a marked increase in nuclear pTyr-STAT1 (+301 +/- 61%) and pTyr-STAT3 (+253 +/- 60%) 30 min after ischemic PC, which was associated with redistribution of STAT1 and STAT3 from the cytosolic to the nuclear fraction and with an increase in STAT1 and STAT3 gamma-IFN activation site DNA-binding activity (+606 +/- 64%), indicating activation of STAT1 and STAT3. No nuclear translocation or tyrosine phosphorylation of STAT2, STAT4, STAT5A, STAT5B, or STAT6 was observed. Pretreatment with the JAK inhibitor AG-490 20 min before the six occlusion/reperfusion cycles blocked the enhanced tyrosine phosphorylation of JAK1 and JAK2 and the increased tyrosine phosphorylation, nuclear translocation, and enhanced DNA-binding activity of STAT1 and STAT3. The same dose of AG-490 abrogated the protection against myocardial infarction and the concomitant up-regulation of inducible NO synthase (iNOS) protein and activity observed 24 h after ischemic PC. Taken together, these results demonstrate that ischemic PC induces isoform-selective activation of JAK1, JAK2, STAT1, and STAT3, and that ablation of this response impedes the up-regulation of iNOS and the concurrent acquisition of ischemic tolerance. This study demonstrates that the JAK-STAT pathway plays an essential role in the development of late PC. The results reveal a signaling mechanism that underlies the transcriptional up-regulation of the cardiac iNOS gene and the adaptation of the heart to ischemic stress.
We have developed a method that we have called Protein Alpha Shape Similarity Analysis (PASSA), that identifies interaction sites that can be utilised to achieve selectivity towards a protein. We have shown that this method is able to identify residues of tyrosine kinases that interact with known selective inhibitors using the following test cases: Abelson (Abl) kinase in complex with STI-571 and Janus kinase 2 (Jak2) in complex with AG-490. The 3D structures of the tyrosine kinase domains of Tyrosine kinase 2 (Tyk2) and Jak2 have been predicted by homology modelling. Computational docking of AG-490 and a set of tyrphostins known not to inhibit Jak2 indicated that our homology models are able to separate inhibitors from non-inhibitors. PASSA has also been used to identify unique properties of Tyk2. According to our results, interactions with hydrogen acceptors and donors on the following residues can be utilised to achieve selectivity towards Tyk2: Y955, E1053, D1062 and S1063. These residues are placed close to non-conserved hydrophobic pockets. The PASSA results, together with results from Multiple Copy Simultaneous Search (MCSS) were used to suggest functional groups of a selective Tyk2 inhibitor.
The Protein Data Bank (PDB; http://www.rcsb.org/pdb/ ) is the single worldwide archive of structural data of biological macromolecules. This paper describes the goals of the PDB, the systems in place for data deposition and access, how to obtain further information, and near-term plans for the future development of the resource.
PATTY (Programmable ATom TYper) is an algorithm for assigning ''atom types'' to a molecule based on its connection table of atoms and bonds. Its operation is controlled entirely by a rules file created by the user. Each rule contains a ''pattern'', a description in linear notation of a class of chemical substructures which may contain branches or rings. Rules are of two sorts: those which define properties to be used in subsequent rules and those which assign the final atom types. As an example, we present rules for classifying atoms into seven broad types based on their physical properties (e.g. cation, H-bond donor, hydrophobe). This classification has been applied to large databases of three-dimensional modes of druglike compounds. PATTY is very rapid and operates on a variety of hardware platforms.
Methods for alignment of protein sequences typically measure similarity by using a substitution matrix with scores for all possible exchanges of one amino acid with another. The most widely used matrices are based on the Dayhoff model of evolutionary rates. Using a different approach, we have derived substitution matrices from about 2000 blocks of aligned sequence segments characterizing more than 500 groups of related proteins. This led to marked improvements in alignments and in searches using queries from each of the groups.
The study of families of protein structures is important in analysing the results of NMR structure determinations and in investigating mechanisms of molecular evolution at the level of conformation. A method is discussed for finding the transformations that mutually superpose an arbitrary number of structures in the least-squares sense given specified atom-to-atom correspondence.
A new method is proposed for determining energetically favorable positions and orientations for functional groups on the surface of proteins with known three-dimensional structure. From 1,000 to 5,000 copies of a functional group are randomly placed in the site and subjected to simultaneous energy minimization and/or quenched molecular dynamics. The resulting functionality maps of a protein receptor site, which can take account of its flexibility, can be used for the analysis of protein ligand interactions and rational drug design. Application of the method to the sialic acid binding site of the influenza coat protein, hemagglutinin, yields functional group minima that correspond with those of the ligand in a cocrystal structure.
A computer adaptable method for finding similarities in the amino acid sequences of two proteins has been developed. From these findings it is possible to determine whether significant homology exists between the proteins. This information is used to trace their possible evolutionary development.The maximum match is a number dependent upon the similarity of the sequences. One of its definitions is the largest number of amino acids of one protein that can be matched with those of a second protein allowing for all possible interruptions in either of the sequences. While the interruptions give rise to a very large number of comparisons, the method efficiently excludes from consideration those comparisons that cannot contribute to the maximum match.Comparisons are made from the smallest unit of significance, a pair of amino acids, one from each protein. All possible pairs are represented by a two-dimensional array, and all possible comparisons are represented by pathways through the array. For this maximum match only certain of the possible pathways must be evaluated. A numerical value, one in this case, is assigned to every cell in the array representing like amino acids. The maximum match is the largest number that would result from summing the cell values of every pathway.
Hematopoiesis is regulated through the interaction of a variety of growth factors with specific receptors of the cytokine receptor superfamily. Although lacking catalytic domains, all the receptors couple ligand binding to the rapid induction of protein tyrosine phosphorylation. This is mediated through a novel family of protein tyrosine kinases termed the Janus kinases (Jaks) which associate with the receptors and are activated following ligand binding. Depending upon the cytokine/receptor system, one or more of the four known Jaks (Jak1, Jak2, Jak3, Tyk2) is/are involved. The activated Jaks phosphorylate both themselves and the receptor subunits, creating docking sites for SH2-containing proteins including SHC, which couples receptor engagement to activation of the ras pathway, and HCP, a protein tyrosine phosphatase which negatively affects the response. In addition, the Jaks phosphorylate one or more of a family of signal transducers and activators of transcription (Stats). Phosphorylation of Stats induces their nuclear translocation and DNA-binding activity. Activation of Stats is independent of activation of the ras pathway and represents a novel signaling pathway correlated with mitogenesis.
Acute lymphoblastic leukaemia (ALL) is the most common cancer of childhood. Despite the progress achieved in its treatment, 20% of cases relapse and no longer respond to chemotherapy. The most common phenotype of ALL cells share surface antigens with very early precursors of B cells and are therefore believed to originate from this lineage. Characterization of the growth requirement of ALL cells indicated that they were dependent on various cytokines, suggesting paracrine and/or autocrine growth regulation. Because many cytokines induce tyrosine phosphorylation in lymphoid progenitor cells, and constitutive tyrosine phosphorylation is commonly observed in B-lineage leukaemias, attempts have been made to develop protein tyrosine kinase (PTK) blockers of leukaemia cell growth. Here we show that leukaemic cells from patients in relapse have constitutively activated Jak-2 PTK. Inhibition of Jak-2 activity by a specific tyrosine kinase blocker, AG-490, selectively blocks leukaemic cell growth in vitro and in vivo by inducing programmed cell death, with no deleterious effect on normal haematopoiesis.
Since the discovery of their physiological roles in cytokine signalling, the Janus kinases (JAKs) and the signal transducers and activators of transcription (STATs) have attracted considerable attention, to the point that the concept of a intracellular signalling pathway, named JAK/STAT, has emerged. As originally defined, this pathway involves ligand-dependent activation of a particular class of receptor-associated tyrosine kinases, the JAK proteins, which phosphorylate themselves and receptor components, creating recruitment sites for STAT transcription factors. The STATs are phosphorylated, they dissociate from the receptor x JAK complex and translocate to the nucleus where they participate in transcriptional gene activation. Although this pathway was found initially to be activated by interferons, it is now known that a large number of cytokines, growth factors and hormonal factors activate JAK and/or STAT proteins. Recent findings have suggested that the interdependence of JAKs and STATs might not be absolute as originally thought.
Recent advances in the biology of multiple myeloma cell growth and survival have suggested new avenues for treatment and potential cure of this disease. Adhesion molecules on the myeloma cell surface mediate their localization in the bone marrow via binding to extracellular matrix proteins and stromal cells. Stromal cell to tumor cell contact and the secretion of transforming growth factor by tumor cells triggers interleukin-6 secretion from stromal cells and paracrine tumor cell growth. CD40 activation of myeloma cells changes their cell surface phenotype, triggers autocrine interleukin-6 secretion, and can regulate myeloma cell cycle in a p53-dependent fashion. Interleukin-6 is both a growth and survival factor for myeloma cells, and delineation of the signaling cascades mediating its effects permits the development of novel therapies either to interrupt growth or trigger apoptosis. New immune therapies offer the opportunity to treat minimal residual disease after stem cell transplantation, thereby improving outcome. Selected donor lymphocyte infusions after allografting and infusion of activated autologous T cells following autografting are examples of adoptive immunotherapy. Myeloma cell to dendritic cell fusions have been used in a vaccination strategy both to prevent and treat myeloma in an animal model, providing the rationale for similar clinical trials in humans. For the first time, a variety of novel treatment strategies derived from advances in understanding the disease pathogenesis offer the potential to achieve long-term disease-free survival in patients with multiple myeloma.
Tyrosine phosphorylation is one of the key covalent modifications that occurs in multicellular organisms as a result of intercellular communication during embryogenesis and maintenance of adult tissues. The enzymes that carry out this modification are the protein tyrosine kinases (PTKs), which catalyze the transfer of the phosphate of ATP to tyrosine residues on protein substrates. Phosphorylation of tyrosine residues modulates enzymatic activity and creates binding sites for the recruitment of downstream signaling proteins. Two classes of PTKs are present in cells: the transmembrane receptor PTKs and the nonreceptor PTKs. Because PTKs are critical components of cellular signaling pathways, their catalytic activity is strictly regulated. Over the past several years, high-resolution structural studies of PTKs have provided a molecular basis for understanding the mechanisms by which receptor and nonreceptor PTKs are regulated. This review will highlight the important results that have emerged from these structural studies.
Protein Alpha Shape (PAS) Dock is a new empirical score function suitable for virtual library screening using homology modelled protein structures. Here, the score function is used in combination with the geometry search method Tabu search. A description of the protein binding site is generated using gaussian property fields like in Protein Alpha Shape Similarity Analysis (PASSA). Gaussian property fields are also used to describe the ligand properties. The overlap between the receptor and ligand hydrophilicity and lipophilicity fields is maximised, while minimising steric clashes. Gaussian functions introduce a smoothing of the property fields. This makes the score function robust against small structural variations, and therefore suitable for use with homology models. This also makes it less critical to include protein flexibility in the docking calculations. We use a fast and simplified version of the score function in the geometry search, while a more detailed version is used for the final prediction of the binding free energies. This use of a two-level scoring makes PAS-Dock computationally efficient, and well suited for virtual screening. The PAS-Dock score function is trained on 218 X-ray structures of protein- ligand complexes with experimental binding affinities. The performance of PAS-Dock is compared to two other docking methods, AutoDock and MOE-Dock, with respect to both accuracy and computational efficiency. According to this study, PAS-Dock is more computationally efficient than both AutoDock and MOE-Dock, and gives a better prediction of the free energies of binding. PAS-Dock is also more robust against structural variations than AutoDock.
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