Home About us Contact
|
Home About us Contact | ||
|
|
||
Simultaneous Binding (simultaneous + binding)
Selected AbstractsTowards Selective Recognition of Sialic Acid Through Simultaneous Binding to Its cis -Diol and Carboxylate FunctionsEUROPEAN JOURNAL OF ORGANIC CHEMISTRY, Issue 17 2010Martín Regueiro-Figueroa Abstract A series of receptors containing phenylboronic acid and urea or thiourea units have been designed for simultaneous recognition of the cis -diol and carboxylate functions of sialic acids, which are known to be overexpressed on the surfaces of tumor cells. The interaction of the receptors with 5-acetylneuraminic acid (Neu5Ac) and 2-,- O -methyl Neu5Ac (MeNeu5Ac) in DMSO solution has been investigated bymeans of spectrophotometric titrations and 1H, 13C, and 11B NMR spectroscopy. Additionally, we have also investigated the binding of these receptors with competing monosaccharides such as D -(+)-glucose, D -fructose, methyl ,- D -galactoside, and methyl ,- D -mannoside. Our results show that 2-{[3-(4-nitrophenyl)thioureido]methyl}phenylboronic acid (3a) recognizes both Neu5Ac and MeNeu5Ac with good selectivity with regard to the remaining monosaccharides investigated. DFT calculations performed at the B3LYP/6-31G(d) level show that this selectivity is due to a cooperative two-site binding of Neu5Ac through 1) ester formation by interaction at the phenylboronic acid function of the receptor and 2) hydrogen-bond interaction between the thiourea moiety and the carboxylate group of Neu5Ac. Compound 3a can therefore be considered a promising synthon for the design of contrast agents for magnetic resonance imaging of tumors. In contrast, the analogue of 3a containing a urea moiety , compound 3b , displays strong binding to all monosaccharides investigated, due to two-site binding through interaction on the phenylboronic acid function of the receptor and a hydrogen-bond interaction between the urea moiety and the sugar hydroxy groups. [source] The history of sweet taste: not exactly a piece of cakeJOURNAL OF MOLECULAR RECOGNITION, Issue 3 2006Pierandrea Temussi Abstract Understanding the molecular bases of sweet taste is of crucial importance not only in biotechnology but also for its medical implications, since an increasing number of people is affected by food-related diseases like, diabetes, hyperlipemia, caries, that are more or less directly linked to the secondary effects of sugar intake. Despite the interest paid to the field, it is only through the recent identification and functional expression of the receptor for sweet taste that new perspectives have been opened, drastically changing our approach to the development of new sweeteners. We shall give an overview of the field starting from the early days up to discussing the newest developments. After a review of early models of the active site, the mechanisms of interaction of small and macromolecular sweet molecules will be examined in the light of accurate modeling of the sweet taste receptor. The analysis of the homology models of all possible dimers allowed by combinations of the human T1R2 and T1R3 sequences of the sweet receptor and the closed (A) and open (B) conformations of the mGluR1 glutamate receptor shows that only ,type B' sites, either T1R2(B) and T1R3(B), can host the majority of small molecular weight sweeteners. Simultaneous binding to the A and B sites is not possible with two large sweeteners but is possible with a small molecule in site A and a large one in site B. This observation accounted for the first time for the peculiar phenomenon of synergy between some sweeteners. In addition to these two sites, the models showed an external binding site that can host sweet proteins. Copyright © 2006 John Wiley & Sons, Ltd. [source] Generalized fuzzy quantifiers and the modeling of fuzzy branching quantificationINTERNATIONAL JOURNAL OF INTELLIGENT SYSTEMS, Issue 6 2009Ingo Glöckner Lindström (Theoria, 1966; 32:186,195) introduced a very powerful notion of quantifiers, which permits multiplace quantification and the simultaneous binding of several variables. "Branching" quantification was found to be useful by linguists, e.g., for modeling reciprocal constructions like "Most men and most women admire each other." Westerståhl (In Gärdenfors P., editor. Generalized Quantifiers. New York: Reidel; 1987. pp 269,298) showed how to compute the three-place Lindström quantifier for "Q1As and Q2Bs R each other" from the binary quantifiers Q1 and Q2, assuming crisp quantifiers and arguments. In the paper, this basic method will be generalized to vague quantifiers like "many" and fuzzy arguments like "young." A consistent interpretation is achieved by extending the DFS theory of fuzzy quantification (Glöckner, TR97-06, 1997; TR2002-07, (Int J Approx Reason) 2003; 2004; 37(2):93,126), which introduces fuzzy generalized quantifiers in conformance with the original linguistic notion, and controls their interpretation by formal adequacy criteria. The new analysis is important to linguistic data summarization because the full meaning of reciprocal summarizers (e.g., describing factors, which are "correlated" or "associated" with each other), can only be captured by branching quantification. The proofs of all theorems cited in the paper are listed in (Glöckner, TR2002-07, 2003). © 2009 Wiley Periodicals, Inc. [source] Characterization of site I of human serum albumin using spectroscopic analyses: Locational relations between regions Ib and Ic of site IJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 12 2004Keishi Yamasaki Abstract Site I of human serum albumin is an important and complex region for high-affinity binding of drugs. Equilibrium dialysis showed independent binding of dansyl- L -asparagine (DNSA) and n -alkyl p -aminobenzoates (p -ABEs) to regions Ib and Ic, respectively, in the pH range 6.0,9.0. However, individual binding of DNSA increased with pH in the same range. Binding of the four n -alkyl p -ABEs strongly perturbed the circular dichroism spectrum of bound DNSA, and the effect increased with concentration and the number of carbon atoms in the alkyl moiety. A similar effect was observed by increasing pH from 6.0 to 9.0, a pH range in which human serum albumin is known to undergo the neutral-to-base transition. The spectral changes propose spatial orientation changes of DNSA at region Ib. This proposal was supported by increased fluorescence anisotropy values: n -alkyl p -ABEs binding and the pH-dependent conformational change each restricted the mobility of the naphthalene ring of bound DNSA. Despite the similar effects on the spatial orientation of DNSA, clear differences were observed between the effects of n -alkyl p -ABEs and neutral-to-base transition. The former hardly changed the affinity and maximum fluorescence emission wavelength of bound DNSA; in contrast, the latter significantly affected them. The results give new information about site I and, according to our knowledge, represent a new type of ligand interaction, because the binding site of DNSA could be changed by simultaneous binding of the n -alkyl p -ABEs without affecting the binding constant. © 2004 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 93:3004,3012, 2004 [source] Therapeutic control of B cell activation via recruitment of Fc, receptor IIb (CD32B) inhibitory function with a novel bispecific antibody scaffold,ARTHRITIS & RHEUMATISM, Issue 7 2010Maria-Concetta Veri Objective To exploit the physiologic Fc, receptor IIb (CD32B) inhibitory coupling mechanism to control B cell activation by constructing a novel bispecific diabody scaffold, termed a dual-affinity retargeting (DART) molecule, for therapeutic applications. Methods DART molecules were constructed by pairing an Fv region from a monoclonal antibody (mAb) directed against CD32B with an Fv region from a mAb directed against CD79B, the ,-chain of the invariant signal-transducing dimer of the B cell receptor complex. DART molecules were characterized physicochemically and for their ability to simultaneously bind the target receptors in vitro and in intact cells. The ability of the DART molecules to negatively control B cell activation was determined by calcium mobilization, by tyrosine phosphorylation of signaling molecules, and by proliferation and Ig secretion assays. A DART molecule specific for the mouse ortholog of CD32B and CD79B was also constructed and tested for its ability to inhibit B cell proliferation in vitro and to control disease severity in a collagen-induced arthritis (CIA) model. Results DART molecules were able to specifically bind and coligate their target molecules on the surface of B cells and demonstrated a preferential simultaneous binding to both receptors on the same cell. DART molecules triggered the CD32B-mediated inhibitory signaling pathway in activated B cells, which translated into inhibition of B cell proliferation and Ig secretion. A DART molecule directed against the mouse orthologs was effective in inhibiting the development of CIA in DBA/1 mice. Conclusion This innovative bispecific antibody scaffold that simultaneously engages activating and inhibitory receptors enables novel therapeutic approaches for the treatment of rheumatoid arthritis and potentially other autoimmune and inflammatory diseases in humans. [source] Immunomagnetic detection of micrometastatic cells in bone marrow in uveal melanoma patientsACTA OPHTHALMOLOGICA, Issue 8 2009Nils Eide Abstract. Purpose:, Our objective was to introduce immunomagnetic separation (IMS) in ocular research by evaluating the possibility of detecting tumour cells in bone marrow (BM) and peripheral blood (PB) samples and validating the captured cells as melanocytic cells. Methods:, Mononuclear cell (MNC) fractions isolated from BM and PB in uveal melanoma patients were examined for tumour cells using our IMS method. Sheep-anti-mouse IgG antibody-coated super paramagnetic particles were conjugated to an anti-melanoma antibody. Microscopy of the magnetic fraction isolated from MNCs was performed to identify and count the number of bead-rosetted cells. The finding of at least two rosettes with coated beads in a 20-,l fraction of a sample was registered as a positive test. The melanocytic nature of the tumour cells was ascertained with a double labelling procedure using fluorescent microparticles. Results:, Using IMS in a study of 328 patients, tumour cells were at initial diagnosis found in BM and PB in 29.9% and 1.6% of cases, respectively. In positive samples, a median of 56 tumour cells (range 2,500) were identified. The captured cells were documented to be of melanocytic origin by the simultaneous binding of fluorescent beads coated with another melanoma-associated antibody. Conclusions:, The IMS method was sensitive and efficient in the detection of occult melanoma tumour cells in BM. The validity of the immunomagnetic technique was strengthened by verifying the melanocytic characteristics of the isolated cells. The IMS procedure identifies intact, vital tumour cells, permitting further molecular characterization, an advantage which makes this method attractive for extended use. The clinical relevance of the findings will be further investigated in follow-up studies with repeated sampling and characterization of the isolated tumour cells. [source] pH-Controllable Supramolecular SystemsCHEMISTRY - AN ASIAN JOURNAL, Issue 3 2009Ken Cham-Fai Leung Prof. Abstract Proton, all that matters! This Focus Review surveys representative examples of pH-controllable supramolecular systems with interesting features and state-of-the-art applications, which can lead to the construction of meaningful molecular machines for electronic and biological applications that can be controlled by simple perturbation with acid and base. This Focus Review surveys representative examples of pH-controllable supramolecular systems with interesting features and state-of-the-art applications such as 1),conformational changes within individual molecules; 2),folding/unfolding of polymers; 3),simultaneous binding of cations and anions; 4),logic function; 5),ON,OFF switchable colorimetric sensing; 6),translocation of macrocycle-in-rotaxane molecules; 7),large-scale movement within molecules; and 8),regulation of the substrate flow in nanocontainers. In particular, systems will be discussed that involve: pH-induced conformational changes of a resorcinarene cavitand and a bis(iron porphyrin) complex; pH control in assembly and disassembly of supramolecular systems stabilized with different major noncovalent interactions; pH-driven movements of interlocked molecules involving rotaxanes, molecular elevators, and molecular muscles; and, finally, multicomponent supramolecular systems immobilized on solid supports as pH-responsive nanovalves for the controlled release of specific substrates. Recent advances in the understanding of pH-controllable supramolecular systems have led to the construction of meaningful molecular machines for electronic and biological applications that are amenable to control by simple perturbation with acids and bases. [source] | |||||||||||||