Library Of Building Blocks Research Articles

Chiral Acylation with N-(Protected α-Aminoacyl)benzotriazoles for Advantageous Syntheses of Peptides and Peptide Conjugates

N-(Protected α-aminoacyl)benzotriazoles are efficient intermediates for N- and O-aminoacylation. These intermediates enable fast preparations of biologically relevant peptides and peptide conjugates in high yields and purity, under mild reaction conditions, with full retention of the original chirality. The developed methodology allows simple solution- and solid-phase preparative techniques to generate complex peptides and peptide conjugates and serves as a platform for generating diverse medicinal chemistry building block libraries involving amino acid and heterocyclic moieties crucial for drug development. 1 Introduction 1.1 Background to Peptide Synthesis 1.2 Preparation of N-(Protected α-Aminoacyl)benzotriazoles 2 Peptide Coupling with Chiral N-(Protected α-Amino-acyl)benzotriazoles 2.1 Preparation of Dipeptides 2.2 Preparation of Tripeptides 2.2.1 Tripeptides by the Fragment-Coupling Procedure 2.2.2 Peptides by the Stepwise-Coupling Procedure 2.3 Preparation of Dipeptides Involving Sterically Hindered Amino Acids 2.4 Microwave-Assisted Solid-Phase Peptide Synthesis Utilizing N-(Protected α-Aminoacyl)benzotriazoles 3 Other N-Acylations Using Benzotriazole-Activated Intermediates 3.1 Glyco-Amino-Acids and Glycopeptides 3.2 Fluorescent Amino Acids and Peptides 3.3 Monosaccharide-Based Water-Soluble Fluorescent Tags 3.4 Chiral Peptide Nucleic Acid (PNA) Monomers with Modified Backbones 3.5 Heterocyclic Amines 4 O-Aminoacylation with Chiral N-(Protected α-Aminoacyl)benzotriazoles 4.1 Steroid Esters of α-Amino Acids 4.2 Terpene Esters of α-Amino Acids and Esters Derived from Long-Chain Alcohols 4.3 O-(Aminoacyl)sugar Conjugates 5 Conclusion.

Software Platform for High-Throughput Glycomics

Mass spectrometry (MS) is a key tool for structural analysis of oligosaccharides because of its high accuracy, sensitivity, and speed on one hand and because of the general and flexible protocols on the other. In glycomics projects the analysis of mass spectra is the speed determining step because, unlike in proteomics, software platforms for high-throughput glycan mass spectra interpretation are not fully automated and still depend on highly specialized knowledge. For the publicly available software, initial steps for manual MS data preprocessing are required mostly considering operations with glycan structures already stored in databases. In particular, monoisotopic peaks have to be manually determined or imported. In this contribution we describe our development of a platform for MS data evaluation in glycomics that demands only a low human intervention. The proposed platform named SysBioWare is constructed to allow import of the raw MS data to the spectrum browser and to perform isotopic grouping of detected peaks after de-noising and wavelet analysis. Monoisotopic m/z values render peak list association with the raw MS spectrum and allow compositional assignment according to the tuned building block library. This platform has been applied to human urine glycome as a potent tool for rapid assignment of already known or/and novel structures.

Fragment-based ligand discovery

From home building and decor to mass production, modular design is a standard feature of the modern age. The concept also promises to define drug discovery efforts in the near future, as a wide range of methodologies, from NMR to X-ray crystallography, are being adapted to high-throughput platforms. In particular, "fragment-based ligand discovery" describes the laboratory-driven evolution of drugs from libraries of chemical building blocks. "Evolution" is an apt word for the process, as a wide array of methods are used to define how compound fragments can be best fit into the binding sites of medically relevant target biomolecules. A number of compounds that evolved from fragments have entered the clinic, and the approach is increasingly accepted as an additional route to identifying new hit compounds in pharmaceutical discovery and inhibitor design.

High-throughput synthesis of azide libraries suitable for direct “click” chemistry and in situ screening

A key challenge in current drug discovery is the development of high-throughput (HT) amenable chemical reactions that allow rapid synthesis of diverse chemical libraries of enzyme inhibitors. The Cu(I)-catalyzed, 1,3-dipolar cycloaddition between an azide and an alkyne, better known as "click chemistry", is one such method that has received the most attention in recent years. Despite its popularity, there is still a lack of robust and efficient chemical strategies that give access to diverse libraries of azide-containing building blocks (key components in click chemistry). We report herein a highly robust and efficient strategy for high-throughput synthesis of a 325-member azide library. The method is highlighted by its simplicity and product purity. The utility of the library is demonstrated with the subsequent "click" synthesis of the corresponding bidentate inhibitors against PTP1B.

Next-generation networks application traffic modeling

One of the key selling points of the next-generation network (NGN) architecture is that it facilitates the rapid deployment of numerous applications onto the same core infrastructure. Before this advantage can be fully realized, however, new methods for traffic estimation are needed to assess the performance impact of new applications and ensure adequate quality of service (QoS). We have created a method to assist network operators with such estimates as part of comprehensive design, capacity planning, or business case analyses. The method identifies the key input parameters that impact traffic, provides a library of application building blocks, assembles them to model new applications quickly, and provides a method for calculating the aggregate signaling and bearer traffic for a given set of applications. In this way, a new network model for each application can be created quickly, and the impact of introducing a new set of applications can be estimated without requiring detailed systems engineering expertise on each aspect of the network.

Probing gorge dimensions of cholinesterases by freeze-frame click chemistry

Freeze-frame click chemistry is a proven approach for design in situ of high affinity ligands from bioorthogonal, reactive building blocks and macromolecular template targets. We recently described in situ design of femtomolar reversible inhibitors of fish and mammalian acetylcholinesterases (EC 3.1.1.7; AChEs) using several different libraries of acetylene and azide building blocks. Active center gorge geometries of those AChEs are rather similar and identical triazole inhibitors were detected in situ when incubating the same building block libraries in different AChEs. Drosophila melanogaster AChE crystal structure and other insect AChE homology models differ more in their overall 3D structure than other members of the cholinesterase family. The portion of the gorge proximal to the catalytic triad and choline binding site has a ∼50% reduction in volume, and the gorge entrance at the peripheral anionic site (PAS) is more constricted than in the fish and mammalian AChEs. In this communication we describe rationale for using purified recombinant Drosophila AChE as a template for in situ reaction of tacrine and propidium based libraries of acetylene and azide building blocks. The structures of resulting triazole inhibitors synthesized in situ are expected to differ appreciably from the fish and mammalian AChEs. While the latter AChEs exclusively promote synthesis of syn-substituted triazoles, the best Drosophila AChE triazole inhibitors were always anti-substituted. The anti-regioisomer triazoles were by about one order of magnitude better inhibitors of Drosophila than mammalian and fish AChEs. Moreover, the preferred site of acetylene + azide reaction in insect AChE and the resulting triazole ring formation shifts from near the base of the gorge to closer to its rim due to substantial differences of the gorge geometry in Drosophila AChE. Thus, in addition to synthesizing high affinity, lead inhibitors in situ, freeze-frame, click chemistry has capacity to generate species-specific AChE ligands that conform to the determinants in the gorge.

9.3.3 Simulation‐Based Design Using SysML Part 2: Celebrating Diversity by Example

AbstractThese two companion papers present foundational principles of parametrics in OMG SysML™ and their application to simulation‐based design. Parametrics capabilities have been included in SysML to support integrating engineering analysis with system requirements, behavior, and structure models. This Part 2 paper walks through SysML models for a benchmark tutorial on analysis templates utilizing an airframe system component called a flap linkage. This example highlights how engineering analysis models, such as stress models, are captured in SysML, and then executed by external tools including math solvers and finite element analysis solvers.We summarize the multi‐representation architecture (MRA) method and how its simulation knowledge patterns support computing environments having a diversity of analysis fidelities, physical behaviors, solution methods, and CAD/CAE tools. SysML and composable object (COB) techniques described in Part 1 together provide the MRA with graphical modeling languages, executable parametrics, and reusable, modular, multi‐directional capabilities.We also demonstrate additional SysML modeling concepts, including packages, building block libraries, and requirements‐verification‐simulation interrelationships. Results indicate that SysML offers significant promise as a unifying language for a variety of models—from top‐level system models to discipline‐specific leaf‐level models.

Designing a Nanotube Using Naturally Occurring Protein Building Blocks

Here our goal is to carry out nanotube design using naturally occurring protein building blocks. Inspection of the protein structural database reveals the richness of the conformations of proteins, their parts, and their chemistry. Given target functional protein nanotube geometry, our strategy involves scanning a library of candidate building blocks, combinatorially assembling them into the shape and testing its stability. Since self-assembly takes place on time scales not affordable for computations, here we propose a strategy for the very first step in protein nanotube design: we map the candidate building blocks onto a planar sheet and wrap the sheet around a cylinder with the target dimensions. We provide examples of three nanotubes, two peptide and one protein, in atomistic model detail for which there are experimental data. The nanotube models can be used to verify a nanostructure observed by low-resolution experiments, and to study the mechanism of tube formation.

The Role of Race and Genetics in Health Disparities Research

Over the past decade, 2 powerful scientific movements in the United States, population genetics and health disparities research, have re-ignited a contentious debate on the complex relationships between genes, race, and disease.1–3 The debate is fueled by the Human Genome Project, the increased technological capacity to map the entire human genome (the library of DNA building blocks), and the concerted national efforts to reduce racial disparities in health and health care. Many scientists believe that an understanding of the unique patterns of genes across patient populations defined by race will help identify populations at risk of developing particular diseases and ultimately enable the medical profession to tailor preventive medicine and therapies to those most likely to respond.4 A central premise of this field of investigation is that race is an inherent biological characteristic that accurately reflects human ancestry and the flow of common threads of genetic material in biologically distinct populations over time and geography. Health disparities research focuses on understanding the complex associations between race, health, and health care. Stimulated by the Healthy People 2010 initiative5 and an Institute of Medicine report documenting inequities in medical treatment among racial minorities,6 many health services, social sciences, and public health investigators have come to view race as a social and cultural construct, not a biological construct to be used in studies of race and human illness. Differences of opinion on the appropriate way to apply the construct of race in biomedical and health services research raise 3 important questions for medical and public health practitioners, scientists, policymakers, and funding agencies committed to advancing both biomedical and health disparities research agendas: What are the arguments for and against using a biological definition of race in medical research? What is the best way to articulate a comprehensive health disparities research agenda? What are the current and future roles of genetics in advancing the health disparities research agenda?

Targeting nucleic acid secondary structures with polyamides using an optimized dynamic combinatorial approach.

Reversible disulfide chemistry is used to identify ligands that stabilize either duplex or quadruplex DNA secondary structures from a dynamic combinatorial library of polyamide building blocks (example structure shown). Double-stranded DNA induces a larger amplification than quadruplex DNA, in accordance with the selectivity of the ligands for each DNA target.

Potential folding-function interrelationship in proteins.

The possibility is addressed that protein folding and function may be related via regions that are critical for both folding and function. This approach is based on the building blocks folding model that describes protein folding as binding events of conformationally fluctuating building blocks. Within these, we identify building block fragments that are critical for achieving the native fold. A library of such critical building blocks (CBBs) is constructed. Then, it is asked whether the functionally important residues fall in these CBB fragments. We find that for over two-thirds of the proteins in our library with available functional information, the catalytic or binding site residues lie within the CBB regions. From the evolutionary standpoint, a folding-function relationship is advantageous, since the need to guard against mutations is limited to one region. Furthermore, conformationally similar CBBs are found in globally unrelated proteins with different functions. Hence, substituting CBBs may lead to designed proteins with altered functions. We further find that the CBBs in our library are conformationally unstable.

A REUSE-ORIENTED WORKFLOW DEFINITION LANGUAGE

This paper presents a new formalism for workflow process definition, which combines research in programming languages and in database systems. This formalism is based on creating a library of workflow building blocks, which can be progressively combined and nested to construct complex workflows. Workflows are specified declaratively, using a simple high level language, which allows the dynamic definition of exception handling and events, as well as dynamically overriding workflow definition. This ensures a high degree of flexibility in data and control flow specification, as well as in reuse of workflow specifications to construct other workflows. The resulting workflow execution environment is well suited to supporting cooperative work.

Design of Reconfigurable Machine Tools

In this paper, we present a systematic methodology for designing Reconfigurable Machine Tools (RMTs). The synthesis methodology takes as input a set of functional requirements—a set of process plans and generates a set of kinematically viable reconfigurable machine tools that meet the given design specifications. We present a mathematical framework for synthesis of machine tools using a library of building blocks. The framework is rooted in (a) graph theoretic methods of enumeration of alternate structural configurations and (b) screw theory that enables us to manipulate matrix representations of motions to identify appropriate kinematic building blocks.

Detection and simulation of roof-corner pressure transients

Many practical time series, including pressure signals measured on roof-corners of low-rise buildings in quartering winds, consist of relatively quiescent periods interrupted by intermittent transients. The dyadic wavelet transform is used to detect these transients in pressure time series and a relatively simple pattern classification scheme is used to detect underlying structure in these transients. Statistical analysis of the resulting pattern classes yields a library of signal building blocks, which are useful for detailed characterization of transients inherent to the signals being analyzed. Probability density functions describing the arrival intervals and characteristics of the detected transients are used to synthesize time series that mimic the intermittency of the original signal. In addition, the signal that remains when the detected transients are removed from the original signal is examined to suggest appropriate models for the background noise in the intermittent signal.

Modular generic software system for cellular FMS

The development of complex, flexible manufacturing systems (FMS) is very much dependent on the development of the associated control software. Because of the complexity involved, reliable and quality FMS software with comprehensive functionality and sophistication is difficult to design, implement and maintain. This paper proposes a modular, generic software system. Using the software developed, a range of cellular FMS (CFMS) control software can be generated from a library of well-defined software building blocks. This paper also describes the design of a generic software architecture, covering specifications for the control architecture, controller structure and software platform. Application of the building block concept has addressed the CFMS software problem effectively and the resulting software possesses a high degree of modularity and flexibility.

The structure of an HIV-1 specific cell entry inhibitor in complex with the HIV-1 gp41 trimeric core

The three-dimensional structure of the complex between an HIV-1 cell-entry inhibitor selected from screening a combinatorial library of non-natural building blocks and the central, trimeric, coiled-coil core of HIV-1 gp41 has been determined by X-ray crystallography. The biased combinatorial library was designed to identify ligands binding in nonpolar pockets on the surface of the coiled-coil core of gp41. The crystal structure shows that the non-peptide moiety of the inhibitor binds to the targeted cavity in two different binding modes. This result suggests a strategy for increasing inhibitor potency by use of a second-generation combinatorial library designed to give simultaneous occupancy of both binding sites.

A variety of combinatorially linkable units as disposition:† from a giant icosahedral Keplerate to multi-functional metal–oxide based network structures

In polyoxometalate chemistry a large variety of compounds, clusters and solid-state structures can be formed by linking together metal–oxygen building blocks. Interestingly, reactions based on libraries of virtual building blocks can be planned under appropriate conditions, resulting for instance in the high-yield synthesis of inorganic superfullerenes and giant ring-shaped, electron-rich, mixed-valence polyoxomolybdates with nanosized cavities. The latter species can continue to grow and also can be covalently linked together to form chains as well as layered mesoporous compounds with properties relevant for materials science. The largest polyoxometalate cluster obtained on the basis of such a growth process consists of 248 Mo atoms. Remarkably, such giant ring species can also act as hosts for other clusters forming new types of supramolecular compounds.

Lipophilic propanediamines: New building blocks for combinatorial chemistry

Combinatorial chemists need building block libraries where molecular diversity is taken into account. For this purpose, we describe the synthesis of a library of 2-alkyl and 2-alkoxypropanediamines for which a large scale of lipophilicity is investigated.

A 0.9-V microcontroller for portable applications

A 0.9-1.6-V, 1-MHz, 8-b microcontroller based on the 68HC08 architecture is presented. In addition to standard digital microcontroller functions, the chip features RAM, ROM, phase-locked loop (PLL) clock synthesis, and liquid crystal displays (LCD) drive capabilities operating from the voltage supply range of a single AA or AAA battery. The design used a library of CMOS microcontroller building blocks, converted into a low-voltage technology using unilateral transistors. The design approach was to optimize the conversion strategy for each functional block and to provide new designs when the conversion was insufficient. The chip exceeded specifications with blocks showing full functionality down to 0.7 V.

Efficient VLSI architectures for a high-performance digital image communication system

A typical digital image communication system based on a number of ASIC architectural designs is currently under development. After partitioning the complete system into several stages, each selected algorithm can be implemented on a single ASIC based on an efficient architectural style. The required throughput for high-performance data compression and channel coding has been obtained due to the optimization of the critical path in the architectural design. Input/output (I/O) operations, which create the bottleneck for many image-processing algorithms, are handled by a dedicated I/O interface unit. Construction of each dedicated data path in the architecture is based on a limited parameterizable functional building block (FBB) library. The dedicated data paths have been constructed by partitioning the initial signal flow graph (SFG) into compatible graphs and by matching the graphs in each partition onto a collection of time-multiplexed FBBs. Hierarchically partitioned controllers were used to meet the high-throughput requirements. The ASIC architectures proposed are oriented to broadband integrated services digital networks (B-ISDN) as well as high-performance digital image compression systems.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>