1,721,115 research outputs found
Modeling of Cdc25B dual specifity protein phosphatase inhibitors: Docking of ligands and enzymatic inhibition mechanism
No full textThe Cdc25 dual specificity phosphatases have central roles in coordinating cellular signalling processes and cell proliferation. It has been reported that an improper amplification or activation of these enzymes is a distinctive feature of a number of human cancers, including breast cancers. Thus, the inhibition of Cdc25 phosphatases might provide a novel approach for the discovery of new and selective antitumor agents. By using the crystal structure of the catalytic domain of Cdc25B, structural models for the interaction of various Cdc25B inhibitors (1-13) with the enzyme were generated by computational docking. The parallel use of two efficient and predictive docking programs, AutoDock and GOLD, allowed mutual validation of the predicted binding poses. To evaluate their quality, the models were validated with known structure-activity relationships and site-directed mutagenesis data. The results provide an improved basis for structure-based ligand design and suggest a possible explanation for the inhibition mechanism of the examined Cdc25B ligands. We suggest that the recurring motif of a tight interaction between the inhibitor and the two arginine residues, 482 and 544, is of prime importance for reversible enzyme inhibition. In contrast, the irreversible inhibition mechanism of 1-4 seems to be associated with the close vicinity of the quinone ring and the Cys473 catalytic thiolate. We believe that this extensive study might provide useful hints to guide the development of new potent Cdc25B inhibitors as novel anticancer drugs. © 2006 Wiley-VCH Verlag GmbH & Co. KGaA
From the Pharmacophore to the Homology Model of the Benzodiazepine Receptor: The Indolyglyoxylamides Affair
No full textInteraction between the so-called benzodiazepine receptor (BzR) and the chemically heterogeneous class of its ligands is still one of the most challenging objects of theoretical studies. In the mid-90s our group began to collaborate with Prof. Antonio Da Settimo and coworkers to a project of synthesis and biological evaluation of indolylglyoxylamides designed as BzR ligands. Herein we review our efforts in designing these compounds and in interpreting their structure-affinity relationships. Our investigations were carried out for years by adopting the pharmacophore/topological model for BzR ligands set up by Cook's group. In an attempt to rationalize some puzzling structure-affinity relationships we speculated in 1998 that our ligands interact with the BzR by assuming one of two alternative binding modes (called "A" and "B") depending on whether or not they were substituted at the 5-position of the indole nucleus. Such a model received support from a considerable amount of experimental data accumulated throughout our researches. About a decade later, docking calculations performed on a homology-built model of the α 1 BzR subtype were found in agreement with the hypothesis of mode A and mode B of binding accessible to 5-H and, respectively, 5-Cl/NO 2 indole derivatives. © 2012 Bentham Science Publishers
Identification of novel beta-secretase inhibitors through the inclusion of protein flexibility in virtual screening calculations
No full textCharacterizing the 1,4-dihydropyridines binding interactions in the L-type Ca2+ channel: Model construction and docking calculations
No full textL-type Ca2+ channels (LCC) are membrane heteromultimeric proteins that allow the selective entrance of Ca2+ ions into excitable cells upon membrane depolarization. Despite the large amount of compounds (1,4-dihydropyridines, phenylalkylamines, and benzothiazepines) that impede the passage of Ca2+ ions through the channel, it is still not clear how these molecules bind to LCC at an atomic level. In this study, a 3D model of the central pore of LCC was constructed using the X-ray structure of the KcsA K+ channel as template. The resulting LCC model was then used to dock nine different DHPs to shed light on their binding mode. The accordance between the developed model and several experimental data gives us the confidence to propose our model as a valuable platform for future studies aimed at the identification of new potent and LCC-selective ligands. © 2007 American Chemical Society
A balance between elongation and trimming regulates telomere stability in stem cells
No full textTelomere length maintenance ensures self-renewal of human embryonic stem cells (hESCs) and induced pluripotent stem cells (hiPSCs); however, the mechanisms governing telomere length homeostasis in these cell types are unclear. Here, we report that telomere length is determined by the balance between telomere elongation, which is mediated by telomerase, and telomere trimming, which is controlled by XRCC3 and Nbsi, homologous recombination proteins that generate single-stranded C-rich telomeric DNA and double-stranded telomeric circular DNA (T-circles), respectively. We found that reprogramming of differentiated cells induces T-circle and single-stranded C-rich telomeric DNA accumulation, indicating the activation of telomere trimming pathways that compensate telomerase-dependent telomere elongation in hiPSCs. Excessive telomere elongation compromises telomere stability and promotes the formation of partially single-stranded telomeric DNA circles (C-circles) in hESCs, suggesting heightened sensitivity of stem cells to replication stress at overly long telomeres. Thus, tight control of telomere length homeostasis is essential to maintain telomere stability in hESCs
The First Sphingosine 1-Phosphate Lyase Inhibitors against Multiple Sclerosis: A Successful Drug Discovery Tale
No full textModulation of sphingosine 1-phosphate (S1P) signaling represents a solid opportunity for multiple sclerosis (MS) treatment. In this issue, a team at Novartis reports on the identification of the first direct S1P lyase (S1PL) inhibitors as new MS agents. One of the most potent inhibitors reported in their work was demonstrated to be orally bioavailable and fully protective in a MS disease animal model. This work represents an outstanding example of a drug discovery campaign that started with the target identification and validation and culminated with the preclinical tests on animal disease models © 2014 American Chemical Society
Modeling of Cdc25B Dual Specifity Protein Phosphatase Inhibitors: Docking of Ligands and Enzymatic Inhibition Mechanism
No full textThe Cdc25 dual specificity phosphatases have central roles in coordinating cellular signalling processes and cell proliferation. It has been reported that an improper amplification or activation of these enzymes is a distinctive feature of a number of human cancers, including breast cancers. Thus, the inhibition of Cdc25 phosphatases might provide a novel approach for the discovery of new and selective antitumor agents. By using the crystal structure of the catalytic domain of Cdc25B, structural models for the interaction of various Cdc25B inhibitors (1-13) with the enzyme were generated by computational docking. The parallel use of two efficient and predictive docking programs, AutoDock and GOLD, allowed mutual validation of the predicted binding poses. To evaluate their quality, the models were validated with known structure-activity relationships and site-directed mutagenesis data. The results provide an improved basis for structure-based ligand design and suggest a possible explanation for the inhibition mechanism of the examined Cdc25B ligands. We suggest that the recurring motif of a tight interaction between the inhibitor and the two arginine residues, 482 and 544, is of prime importance for reversible enzyme inhibition. In contrast, the irreversible inhibition mechanism of 1-4 seems to be associated with the close vicinity of the quinone ring and the Cys473 catalytic thiolate. We believe that this extensive study might provide useful hints to guide the development of new potent Cdc25B inhibitors as novel anticancer drugs
Architecture of the Human Urotensin II Receptor: Comparison of the Binding Domains of Peptide and Non-Peptide Urotensin II Agonists
No full textThe human urotensin II receptor (h-UTR) is a member of the family of rhodopsin-like G-protein-coupled receptors (GPCRs) involved in the modulation of the functionality of many tissues and organs. Recently the urotensin-II (UII) neuropeptide, which is a potent vasoconstrictor in mammals and it is postulated to play a central role in cardiovascular homeostasis, has been identified as an agonist of the UII receptor. To elucidate the receptor's molecular recognition, a h-UTR model was constructed by homology modeling using the 2.6 A crystal structure of bovine rhodopsin as a template and subsequently refined by molecular dynamics simulations. The molecular recognition of h-UTR was probed by automated docking of P5U, a potent UII peptide agonist, as well as of the non-peptide compounds 1-4. We believe that this new model of the h-UTR provides the means for understanding the ligand's potency and for facilitating the design of novel and more potent UII ligands
Development of novel 1,4-benzodiazepine-based Michael acceptors as antitrypanosomal agents
No full textNovel 1,4-benzodiazepines, endowed with a Michael acceptor moiety, were designed taking advantage of a computational prediction of their pharmacokinetic parameters. Among all the synthesized derivatives, we identified a new lead compound (i.e., 4a), bearing a vinyl ketone warhead and endowed with a promising antitrypanosomal activity against Trypanosoma brucei brucei (IC50 = 5.29 μM), coupled with a lack of cytotoxicity towards mammalian cells (TC50>100 μM)
Ensemble-docking approach on BACE-1: Pharmacophore perception and guidelines for drug design
No full textβ-Secretase (BACE-1), a key enzyme in the etiopathogenesis and progression of Alzheimer Disease, is the focus of medicinal chemistry efforts both in the pharmaceutical industry and in academia. Despite the availability of diverse peptidomimetic BACE-1 inhibitors, nonpeptidic compounds suitable for oral delivery and transport across the blood brain barrier are in great demand. Herein, a number of active and structurally diverse inhibitors were selected and subjected to an ensemble-docking process into five BACE-1 X-ray structures. The calculated bioactive conformations of these inhibitors allowed us to build an exhaustive pharmacophore model, which captures both the common geometric and electronic features essential for enzyme inhibition. The model is intended to aid the rational design of new BACE-1 inhibitors. Furthermore, a comparison of BACE/cathepsin D X-ray structures was made to provide guidelines for the design of BACE-selective inhibitors. © 2007 Wiley-VCH Verlag GmbH& Co. KGaA
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