The Molecular Recognition of DNA by Novel Heterocycles PDF Download

Author: Michael Anthony Marques
Publisher:
ISBN:
Category : Electronic dissertations
Languages : en
Pages : 648

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Author:
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Category :
Languages : en
Pages : 7

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Category : Cations
Languages : en
Pages :

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DB921 and DB911 are biphenyl-benzimidazole-diamidine isomers with a central para- and meta-substituted phenyl group, respectively. Unexpectedly, linear DB921 has much stronger binding affinity with DNA than its curved isomer, DB911. This is quite surprising and intriguing since DB911 has the classical curved shape generally required for strong minor groove binding while DB921 clearly does not match the groove shape. Several biophysical techniques including thermal melting (Tm), circular dichroism (CD), biosensor-surface plasmon resonance (SPR), and isothermal titration calorimetry (ITC) have been utilized to investigate the interactions between these compounds and DNA. The structure of the DB921-DNA complex reveals that DB921 binds to DNA with a reduced twist of the biphenyl for better fit of DB921 into the minor groove. A bound water molecule complements the curvature of DB921 and contributes for tight binding by forming H-bonds with both DNA and DB921. Structure-affinity relationship studies of a series of DB921 analogs show that the benzimidazole group is one of the key groups of DB921 for its strong binding to the minor groove. Thermodynamic studies show that the stronger binding of DB921 is due to a more favorable binding enthalpy compared to DB911 even though the complex formation with DNA for these compounds are all predominantly entropically driven. DB921 also has more negative heat capacity change than DB911. The initial studies of inhibition of the interaction between an AT hook peptide of HMGA proteins and its target DNA by a set of diamidine AT-minor groove binders using biosensor-SPR technique show that the inhibitory ranking order is consistent with that of binding affinity and linear-shaped DB921 still has excellent inhibitory effects. These heterocyclic cations rapidly inhibit the binding of DBD2 peptide to the DNA and may only block the specific AT binding of the peptide without hindering the non-specific binding interaction. The results of this project have shown that DB921 represents a new novel effective minor groove binder that does not fit the traditional model and is a potential inhibitor for DNA/protein complexes.

Author: Kiyoshi Matsumoto
Publisher: Springer Science & Business Media
ISBN: 3540681892
Category : Science
Languages : en
Pages : 210

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Heterocyclic chemistry is the biggest branch of chemistry covering two-thirds of the chemical literature. This series covers this hot topic of frontier research summarized by reputed scientists in the field.

Author: Christopher Paul Mountford
Publisher:
ISBN:
Category :
Languages : en
Pages : 165

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Author: Nicolas Tilmans
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Category :
Languages : en
Pages :

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Directed evolution of large combinatorial chemistry libraries is an emerging approach for small-molecule discovery. To advance this field, we have developed a DNA-programmed chemistry technique that enables breeding of drug-like compounds over multiple generations. The progeny from each cycle of synthesis, selection, and amplification act as the starting point for a subsequent generation; thus the evolutionary cycle can be iterated. The linkage between genotype and phenotype is accomplished by coupling each unique compound to a DNA gene that programs its synthesis. Here we establish the behavior of our technology using a model selection for kinase substrates. We show that the platform behaves in a predictable manner and that it should be capable of identifying useful molecules from very large compound libraries. We then use the technology to discover novel biologically active small molecules by applying a purifying selection to a naive DNA-programmed library comprising 1.1 billion distinct compounds. Given the comprehensive nature of the combinatorial synthesis and the deep sampling enabled by high throughput sequencing, we can observe the simultaneous enrichment of different chemical families, increasing our chances of identifying a true hit. We have thus identified the first known non-peptidic substrate for protein kinase. This work demonstrates the feasibility to chemically probe the substrate binding sites of kinases. More broadly, we have performed the first directed evolution of a billion member combinatorial library. We anticipate that our approach will lead to the discovery of novel small-molecule affinity reagents, pharmaceutical compound leads, imaging probes and other high-value compounds. This could substantially increase global access to small-molecule reagents, and open up new areas of biological inquiry.

Author:
Publisher:
ISBN:
Category : Dissertations, Academic
Languages : en
Pages : 960

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Author: Vincent Rotello
Publisher: John Wiley & Sons
ISBN: 0470384042
Category : Science
Languages : en
Pages : 492

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State-of-the-art techniques for tapping the vast potential of polymers The use of specific non-covalent interactions to control polymer structure and properties is a rapidly emerging field with applications in diverse disciplines. Molecular Recognition and Polymers covers the fundamental aspects and applications of molecular recognition—in the creation of novel polymeric materials for use in drug delivery, sensors, tissue engineering, molecular imprinting, and other areas. This reference begins by explaining the fundamentals of supramolecular polymers; it progresses to cover polymer formation and self-assembly with a wide variety of examples, and then includes discussions of biomolecular recognition using polymers. With chapters contributed by the foremost experts in their fields, this resource: Provides an integrated resource for supramolecular chemistry, polymer science, and interfacial science Covers advanced, state-of-the-art techniques used in the design and characterization of non-covalent interactions in polymers Illustrates how to tailor the properties of polymeric materials for various applications Stand-alone chapters address specific applications independently for easy reference. This is a premier resource for graduate students and researchers in polymer chemistry, supramolecular chemistry, materials science, and physical organic chemistry.

Author: G.W. Gribble
Publisher: Elsevier
ISBN: 0080515096
Category : Science
Languages : en
Pages : 385

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This volume of Progress in Heterocyclic Chemistry (PHC) is the fourteenth annual review of the literature, covering the work published on important heterocyclic ring systems during 2001. In this volume there are two specialized reviews. The first, by Jan Bergman and Tomasz Janosik, covers their work on sulfur-containing indoles. The second, by David Knight, discusses 5-endo-trig iodocyclisations. The subsequent chapters, arranged by increasing heterocycle ring size, review recent advances in the field of heterocyclic chemistry with emphasis on synthesis and reactions.

Author: Martine Demeunynck
Publisher: John Wiley & Sons
ISBN: 3527605665
Category : Science
Languages : en
Pages : 754

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The development of molecules that selectively bind to nucleic acids has provided many details about DNA and RNA recognition. The range of such substances, such as metal complexes, peptides, oligonucleotides and a wide array of synthetic organic compounds, is as manifold as the functions of nucleic acids. Nucleic acid recognition sequences are often found in the major or minor groove of a double strand, while other typical interactions include intercalation between base pairs or the formation of triple or quadruple helices. One example of a binding mode that has recently been proposed is end stacking on such complex structures as the telomere tetraplex. In this comprehensive book, internationally recognized experts describe in detail the important aspects of nucleic acid binding, and in so doing present impressive approaches to drug design. Since typical substances may be created naturally or synthetically, emphasis is placed on natural products, chemical synthesis, the use of combinatorial libraries, and structural characterization. The whole is rounded off by contributions on molecular modeling, as well as investigations into the way in which any given drug interacts with its nucleic acid recognition site.