97,559 research outputs found
JACOBSON RADICAL ALGEBRAS WITH QUADRATIC GROWTH
No full textWe show that over every countable algebraically closed field K there exists a finitely generated K-algebra that is Jacobson radical, infinite-dimensional, generated by two elements, graded and has quadratic growth. We also propose a way of constructing examples of algebras with quadratic growth that satisfy special types of relations.</p
Medicinal chemistry of the a(3) adenosine receptor: agonists, antagonists, and receptor engineering
No full textA(3) adenosine receptor (A(3)AR) ligands have been modified to optimize their interaction with the A(3)AR. Most of these modifications have been made to the N(6) and C2 positions of adenine as well as the ribose moiety, and using a combination of these substitutions leads to the most efficacious, selective, and potent ligands. A(3)AR agonists such as IB-MECA and Cl-IB-MECA are now advancing into Phase II clinical trials for treatments targeting diseases such as cancer, arthritis, and psoriasis. Also, a wide number of compounds exerting high potency and selectivity in antagonizing the human (h)A(3)AR have been discovered. These molecules are generally characterized by a notable structural diversity, taking into account that aromatic nitrogen-containing monocyclic (thiazoles and thiadiazoles), bicyclic (isoquinoline, quinozalines, (aza)adenines), tricyclic systems (pyrazoloquinolines, triazoloquinoxalines, pyrazolotriazolopyrimidines, triazolopurines, tricyclic xanthines) and nucleoside derivatives have been identified as potent and selective A(3)AR antagonists. Probably due to the "enigmatic" physiological role of A(3)AR, whose activation may produce opposite effects (for example, concerning tissue protection in inflammatory and cancer cells) and may produce effects that are species dependent, only a few molecules have reached preclinical investigation. Indeed, the most advanced A(3)AR antagonists remain in preclinical testing. Among the antagonists described above, compound OT-7999 is expected to enter clinical trials for the treatment of glaucoma, while several thiazole derivatives are in development as antiallergic, antiasthmatic and/or antiinflammatory drugs
Structural Probing and Molecular Modeling of the A3 Adenosine Receptor: A Focus on Agonist Binding
No full textAdenosine is an endogenous modulator exerting its functions through the activation of four adenosine receptor (AR) subtypes, termed A1, A2A, A2B and A3, which belong to the G protein-coupled receptor (GPCR) superfamily. The human A3AR (hA3AR) subtype is implicated in several cytoprotective functions. Therefore, hA3AR modulators, and in particular agonists, are sought for their potential application as anti-inflammatory, anticancer, and cardioprotective agents. Structure-based molecular modeling techniques have been applied over the years to rationalize the structure–activity relationships (SARs) of newly emerged A3AR ligands, guide the subsequent lead optimization, and interpret site-directed mutagenesis (SDM) data from a molecular perspective. In this review, we showcase selected modeling-based and guided strategies that were applied to elucidate the binding of agonists to the A3AR and discuss the challenges associated with an accurate prediction of the receptor extracellular vestibule through homology modeling from the available X-ray templates
Proper Ferroelectricity in the Dion?Jacobson Material CsBi2Ti2NbO10: Experiment and Theory
No full textA diverse range of materials and properties are exhibited by layered perovskites. We report on the synthesis, characterization, and computational investigation of a new ferroelectric?CsBi2Ti2NbO10, an n = 3 member of the Dion?Jacobson (DJ) family. Structural studies using variable temperature neutron powder diffraction indicate that a combination of octahedral rotations and polar displacements result in the polar structure. Density functional theory calculations reveal that the wider perovskite blocks in CsBi2Ti2NbO0 stabilize proper ferroelectricity, in contrast to the hybrid-improper ferroelectricity reported for all other DJ phases. Our results raise the possibility of a new class of proper ferroelectric materials analogous to the well-known Aurivillius phases
Breakthrough in GPCR Crystallography and Its Impact on Computer-Aided Drug Design
No full textRecent crystallographic structures of G protein-coupled receptors (GPCRs) have greatly advanced our understanding of the recognition of their diverse agonist and antagonist ligands. We illustrate here how this applies to A2A adenosine receptors (ARs) and to P2Y1 and P2Y12 receptors (P2YRs) for ADP. These X-ray structures have impacted the medicinal chemistry aimed at discovering new ligands for these two receptor families, including receptors that have not yet been crystallized but are closely related to the known structures. In this Chapter, we discuss recent structure-based drug design projects that led to the discovery of: (a) novel A3AR agonists based on a highly rigidified (N)-methanocarba scaffold for the treatment of chronic neuropathic pain and other conditions, (b) fluorescent probes of the ARs and P2Y14R, as chemical tools for structural probing of these GPCRs and for improving assay capabilities, and (c) new more drug-like antagonists of the inflammation-related P2Y14R. We also describe the computationally enabled molecular recognition of positive (for A3AR) and negative (P2Y1R) allosteric modulators that in some cases are shown to be consistent with structure-activity relationship (SAR) data. Thus, computational modeling has become an essential tool for the design of purine receptor ligands
Selected Bibliography of Harold K. Jacobson
No full textA bibliography of Professor Harold K. Jacobson\u27s selected work
In Silico Drug Design for Purinergic GPCRs: Overview on Molecular Dynamics Applied to Adenosine and P2Y Receptors
No full textMolecular modeling has contributed to drug discovery for purinergic GPCRs, including adenosine receptors (ARs) and P2Y receptors (P2YRs). Experimental structures and homology modeling have proven to be useful in understanding and predicting structure activity relationships (SAR) of agonists and antagonists. This review provides an excursus on molecular dynamics (MD) simulations applied to ARs and P2YRs. The binding modes of newly synthesized A1AR- and A3AR-selective nucleoside derivatives, potentially of use against depression and inflammation, respectively, have been predicted to recapitulate their SAR and the species dependence of A3AR affinity. P2Y12R and P2Y1R crystallographic structures, respectively, have provided a detailed understanding of the recognition of anti-inflammatory P2Y14R antagonists and a large group of allosteric and orthosteric antagonists of P2Y1R, an antithrombotic and neuroprotective target. MD of A2AAR (an anticancer and neuroprotective target), A3AR, and P2Y1R has identified microswitches that are putatively involved in receptor activation. The approach pathways of different ligands toward A2AAR and P2Y1R binding sites have also been explored. A1AR, A2AAR, and A3AR were utilizes to study allosteric phenomena, but locating the binding site of structurally diverse allosteric modulators, such as an A3AR enhancer LUF6000, is challenging. Ligand residence time, a predictor of in vivo efficacy, and the structural role of water were investigated through A2AAR MD simulations. Thus, new MD and other modeling algorithms have contributed to purinergic GPCR drug discovery
Purinergic Signaling: Impact of GPCR Structures on Rational Drug Design
No full textThe purinergic signaling system includes membrane-bound receptors for extracellular purines and pyrimidines, and enzymes/transporters that regulate receptor activation by endogenous agonists. Receptors include: adenosine (A1, A2A, A2B, and A3) and P2Y (P2Y1, P2Y2, P2Y4, P2Y6, P2Y11, P2Y12, P2Y13, and P2Y14) receptors (all GPCRs), as well as P2X receptors (ion channels). Receptor activation, especially accompanying physiological stress or damage, creates a temporal sequence of signaling to counteract this stress and either mobilize (P2Rs) or suppress (ARs) immune responses. Thus, modulation of this large signaling family has broad potential for treating chronic diseases. Experimentally determined structures represent each of the three receptor families. We focus on selective purinergic agonists (A1, A3), antagonists (A3, P2Y14), and allosteric modulators (P2Y1, A3). Examples of applying structure-based design, including the rational modification of known ligands, are presented for antithrombotic P2Y1R antagonists and anti-inflammatory P2Y14R antagonists and A3AR agonists. A3AR agonists are a potential, nonaddictive treatment for chronic neuropathic pain
Survey of ribose ring pucker of signaling nucleosides and nucleotides
No full textThe ribose of protein-bound nucleosides and nucleotides displays preferred conformations (usually either North or South), which can be exploited to design enhanced analogs having chemically fixed conformations. We introduce a computational protocol for assembling data from the protein database (PDB) on the ribose and ribose-like conformation of small molecule ligands when complexed with purinergic signaling proteins (including receptors, enzymes and transporters, and related intracellular pathways). Some targets prefer exclusively North (adenosine and P2Y1 receptors, CD73, adenosine kinase ATP/ADP-binding site, adenosine deaminase), others prefer South (P2Y12 receptor, E-NTPDase2) or East (adenosine kinase substrates), while others (P2XRs) allow various conformations
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