Kinase packing defects as drug targets.
Ontology highlight
ABSTRACT:
SUBMITTER: Crespo A
PROVIDER: S-EPMC2136416 | biostudies-literature | 2007 Nov
REPOSITORIES: biostudies-literature
Publications
Kinase packing defects as drug targets.
Crespo Alejandro A Fernández Ariel A
Drug discovery today 20071030 21-22
Protein kinases constitute major targets in molecular cancer therapy. The structural conservation of kinases causes specificity problems in most drug inhibitors, often resulting in dangerous side effects. Here we survey recent approaches in drug design that exploit a molecular marker for specificity: the pattern of packing defects. These packing defects are solvent-exposed intramolecular hydrogen bonds that may be protected by drugs upon association. In this light, we review design strategies to ...[more]
Similar Datasets
Project description:The conservation of structure across homolog proteins often diffuses the impact of drug-based inhibition by promoting alternative protein-ligand associations that may lead to toxic side effects. However, sticky packing defects are typically not conserved across homologs, making them valuable a priori targets to enhance specificity. By introducing a homology to quantify packing differences among proteins, we enable a previously undescribed strategy for the design of highly selective drug inhibitors involving ligands that wrap nonconserved packing defects. The selectivity of these ligands is validated by performing affinity assays on a cancer-related pharmacokinome. Minor reengineering of a powerful inhibitor guided by wrapping differences across its target kinome can selectively direct its impact toward a specific kinase. Thus, nonconserved packing defects may be used as selectivity switches across homolog targets, using spatial displacements of packing defects across aligned protein structures.
| S-EPMC1326172 | biostudies-literature
Project description:The packing of helices spanning lipid bilayers is crucial for the stability and function of alpha-helical membrane proteins. Using a modified Voronoi procedure, we calculated packing densities for helix-helix contacts in membrane spanning domains. Our results show that the transmembrane helices of protein channels and transporters are significantly more loosely packed compared with helices in globular proteins. The observed packing deficiencies of these membrane proteins are also reflected by a higher amount of cavities at functionally important sites. The cavities positioned along the gated pores of membrane channels and transporters are noticeably lined by polar amino acids that should be exposed to the aqueous medium when the protein is in the open state. In contrast, nonpolar amino acids surround the cavities in those protein regions where large rearrangements are supposed to take place, as near the hinge regions of transporters or at restriction sites of protein channels. We presume that the observed deficiencies of helix-helix packing are essential for the helical mobility that sustains the function of many membrane protein channels and transporters.
| S-EPMC1305249 | biostudies-literature
Project description:Two viral proteins, HIV-1 protease and HIV-1 integrase, have been targeted for inhibitor design to prevent assembly and maturation of HIV-1 virions. The enzymatic mechanism of these proteins involves side-chain groups that serve as general acids or bases. Furthermore, catalytic activity requires that water be removed from the microenvironment surrounding the chemical reaction site or be constrained to serve as an activated nucleophile. Here, we identify previously unrecognized structural features that promote water removal from polar catalytic regions. Packing defects in the form of hydrogen bonds that are insufficiently dehydrated intramolecularly, named "dehydrons," are strategically placed in the structure to induce an anhydrous enzymatic pathway. Dehydrons become electrostatically enhanced and stabilized upon further desolvation. Thus, packing defects act synergistically with the polar active groups to enhance the enzymatic electrostatics. However, because dehydrons are sticky, they constitute targets for inhibitor design. We noticed that inhibitors attach to polar surfaces by further desolvating dehydrons, thus blocking the active sites or the sites involved in harnessing the substrate. The dehydrons are thus required for functional reasons, making them suitable targets. The differences in success when targeting HIV-1 protease, feline immunodeficiency virus protease, and HIV-1 integrase are rationalized in terms of the dehydron distribution, revealing possible improvements in the targeting strategy. Principles of design optimization are proposed to create an inhibitor that can be neutralized only at the expense of the loss of catalytic function. The possibility of using drugs that wrap dehydrons to block protein-protein associations is also discussed.
| S-EPMC511032 | biostudies-literature
Project description:The membrane protein packing database (MP:PD) (http://proteinformatics.charite.de/mppd) is a database of helical membrane proteins featuring internal atomic packing densities, cavities and waters. Membrane proteins are not tightly packed but contain a considerable number of internal cavities that differ in volume, polarity and solvent accessibility as well as in their filling with internal water. Internal cavities are supposed to be regions of high physical compressibility. By serving as mobile hydrogen bonding donors or acceptors, internal waters likely facilitate transition between different functional states. Despite these distinct functional roles, internal cavities of helical membrane proteins are not well characterized, mainly because most internal waters are not resolved by crystal structure analysis. Here we combined various computational biophysical techniques to characterize internal cavities, reassign positions of internal waters and calculate internal packing densities of all available helical membrane protein structures and stored them in MP:PD. The database can be searched using keywords and entries can be downloaded. Each entry can be visualized in Provi, a Jmol-based protein viewer that provides an integrated display of low energy waters alongside membrane planes, internal packing density, hydrophobic cavities and hydrogen bonds.
| S-EPMC3965053 | biostudies-literature
Project description:Specific intracellular localization of RAB GTPases has been reported to be dependent on protein factors, but the contribution of the membrane physicochemical properties to this process has been poorly described. Here, we show that three RAB proteins (RAB1/RAB5/RAB6) preferentially bind in vitro to disordered and curved membranes, and that this feature is uniquely dependent on their prenyl group. Our results imply that the addition of a prenyl group confers to RAB proteins, and most probably also to other prenylated proteins, the ability to sense lipid packing defects induced by unsaturated conical-shaped lipids and curvature. Consistently, RAB recruitment increases with the amount of lipid packing defects, further indicating that these defects drive RAB membrane targeting. Membrane binding of RAB35 is also modulated by lipid packing defects but primarily dependent on negatively charged lipids. Our results suggest that a balance between hydrophobic insertion of the prenyl group into lipid packing defects and electrostatic interactions of the RAB C-terminal region with charged membranes tunes the specific intracellular localization of RAB proteins.
| S-EPMC6032855 | biostudies-other
Project description:Current FDA-approved kinase inhibitors cause diverse adverse effects, some of which are due to the mechanism-independent effects of these drugs. Identifying these mechanism-independent interactions could improve drug safety and support drug repurposing. Here, we develop iDTPnd (integrated Drug Target Predictor with negative dataset), a computational approach for large-scale discovery of novel targets for known drugs. For a given drug, we construct a positive structural signature as well as a negative structural signature that captures the weakly conserved structural features of drug-binding sites. To facilitate assessment of unintended targets, iDTPnd also provides a docking-based interaction score and its statistical significance. We confirm the interactions of sorafenib, imatinib, dasatinib, sunitinib, and pazopanib with their known targets at a sensitivity of 52% and a specificity of 55%. We also validate 10 predicted novel targets by using in vitro experiments. Our results suggest that proteins other than kinases, such as nuclear receptors, cytochrome P450, and MHC class I molecules, can also be physiologically relevant targets of kinase inhibitors. Our method is general and broadly applicable for the identification of protein-small molecule interactions, when sufficient drug-target 3D data are available. The code for constructing the structural signatures is available at https://sfb.kaust.edu.sa/Documents/iDTP.zip.
| S-EPMC9403029 | biostudies-literature
Project description:Sensing membrane curvature allows fine-tuning of complex reactions that occur at the surface of membrane-bound organelles. One of the most sensitive membrane curvature sensors, the Amphipathic Lipid Packing Sensor (ALPS) motif, does not seem to recognize the curved surface geometry of membranes per se; rather, it recognizes defects in lipid packing that arise from membrane bending. In a companion paper, we show that these defects can be mimicked by introducing conical lipids in a flat lipid bilayer, in agreement with experimental observations. Here, we use molecular-dynamics (MD) simulations to characterize ALPS binding to such lipid bilayers. The ALPS motif recognizes lipid-packing defects by a conserved mechanism: peptide partitioning is driven by the insertion of hydrophobic residues into large packing defects that are preformed in the bilayer. This insertion induces only minor modifications in the statistical distribution of the free packing defects. ALPS insertion is severely hampered when monounsaturated lipids are replaced by saturated lipids, leading to a decrease in packing defects. We propose that the hypersensitivity of ALPS motifs to lipid packing defects results from the repetitive use of hydrophobic insertions along the monotonous ALPS sequence.
| S-EPMC3566459 | biostudies-other
Project description:Unregulated activation of Src kinases leads to aberrant signalling, uncontrolled growth and differentiation of cancerous cells. Reaching a complete mechanistic understanding of large-scale conformational transformations underlying the activation of kinases could greatly help in the development of therapeutic drugs for the treatment of these pathologies. In principle, the nature of conformational transition could be modelled in silico via atomistic molecular dynamics simulations, although this is very challenging because of the long activation timescales. Here we employ a computational paradigm that couples transition pathway techniques and Markov state model-based massively distributed simulations for mapping the conformational landscape of c-src tyrosine kinase. The computations provide the thermodynamics and kinetics of kinase activation for the first time, and help identify key structural intermediates. Furthermore, the presence of a novel allosteric site in an intermediate state of c-src that could be potentially used for drug design is predicted.
| S-EPMC4465921 | biostudies-literature
Project description:The cellular kinases inhibitory-?B kinase (IKK) ? and Nuclear Factor-?B (NF-?B)-inducing kinase (NIK) are well recognised as key central regulators and drivers of the non-canonical NF-?B cascade and as such dictate the initiation and development of defined transcriptional responses associated with the liberation of p52-RelB and p52-p52 NF-?B dimer complexes. Whilst these kinases and downstream NF-?B complexes transduce pro-inflammatory and growth stimulating signals that contribute to major cellular processes, they also play a key role in the pathogenesis of a number of inflammatory-based conditions and diverse cancer types, which for the latter may be a result of background mutational status. IKK? and NIK, therefore, represent attractive targets for pharmacological intervention. Here, specifically in the cancer setting, we reflect on the potential pathophysiological role(s) of each of these kinases, their associated downstream signalling outcomes and the stimulatory and mutational mechanisms leading to their increased activation. We also consider the downstream coordination of transcriptional events and phenotypic outcomes illustrative of key cancer 'Hallmarks' that are now increasingly perceived to be due to the coordinated recruitment of both NF-?B-dependent as well as NF-?B?independent signalling. Furthermore, as these kinases regulate the transition from hormone-dependent to hormone-independent growth in defined tumour subsets, potential tumour reactivation and major cytokine and chemokine species that may have significant bearing upon tumour-stromal communication and tumour microenvironment it reiterates their potential to be drug targets. Therefore, with the emergence of small molecule kinase inhibitors targeting each of these kinases, we consider medicinal chemistry efforts to date and those evolving that may contribute to the development of viable pharmacological intervention strategies to target a variety of tumour types.
| S-EPMC6210445 | biostudies-literature
Project description:The analysis of the structural organization of lipid bilayers is generally performed across the direction normal to the bilayer/water interface, whereas the surface properties of the bilayer at the interface with water are often neglected. Here, we present PackMem, a bioinformatic tool that performs a topographic analysis of the bilayer surface from various molecular dynamics simulations. PackMem unifies and rationalizes previous analyses based on a Cartesian grid. The grid allows identification of surface regions defined as lipid-packing defects where lipids are loosely packed, leading to cavities in which aliphatic carbons are exposed to the solvent, either deep inside or close to the membrane surface. Examples are provided to show that the abundance of lipid-packing defects varies according to the temperature and to the bilayer composition. Because lipid-packing defects control the adsorption of peripheral proteins with hydrophobic insertions, PackMem is instrumental for us to understand and quantify the adhesive properties of biological membranes as well as their response to mechanical perturbations such as membrane deformation.
| S-EPMC6084522 | biostudies-literature