Dissimilarity-based algorithms for selecting structurally diverse sets of compounds.

This paper commences with a brief introduction to modern techniques for the computational analysis of molecular diversity and the design of combinatorial libraries. It then reviews dissimilarity-based algorithms for the selection of structurally diverse sets of compounds in chemical databases. Procedures are described for selecting a diverse subset of an entire database, and for selecting diverse combinatorial libraries using both reagent-based and product-based selection.     

Proposal of a method for allocation in building-related environmental LCA based on economic parameters

Application and development of the LCA methodology to the context of the building sector makes several building specific considerations necessary, as some key characteristics of products in the building sector differ considerably from those of other industrial sectors. The largest difference is that the service life of a building can stretch over centuries, rather than decades or years as seen for consumer products. The result of the long service life is that it is difficult to obtain accurate data and to make relevant assumptions about future conditions regarding, for example, recycling. These problems have implications on the issue of allocation in the building sector, in the way that several allocation procedures ascribe environmental loads to users of recycled or reused products and materials in the future which are unknown today. The long service life for buildings, building materials and building components, is associated with the introduced concept of a virtual parallel time perspective proposed here, which basically substitutes historical and future processes and values with current data. Further, the production and refining of raw material as a parallel to upgrading of recycled material, normally contains several intermediate products. A suggestion is given for how to determine the comparability of intermediate materials. The suggested method for allocation presented is based on three basic assumptions: (1) If environmental loads are to be allocated to a succeeding product life cycle, the studied actual life cycle has to take responsibility for upgrading of the residual material into secondary resources. (2) Material characteristics and design of products are important factors to estimate the recyclable amount of the material. Therefore, a design factor is suggested using information for inherent material properties combined with information of the product context at the building level. (3) The quality reduction between the materials in two following product life cycles is indicated as the ratio between the market value for the material in the products. The presented method can be a good alternative for handling the problem of open-loop recycling allocation in the context of the building sector if a consensus for the use of the fictive parallel time perspective and the use of the design factor can be established. This as the use of the time perspective and design factor is crucial to be able to deal with the problem of long service lives for buildings and building materials and the specific characteristics of the same building materials and components built into different building contexts.     

Bottom-Up Life-Cycle:Assessment of Product Consumption in Belgium

The present study shows the results and methodology applied to the study of the identification of priority product categories for Belgian product and environmental policy. The main goal of the study was to gather insight into the consumption of products in Belgium and their related life-cycle environmental impacts. The conclusions of this project on the product categories with major environmental contributions can be used to start up working groups involving stakeholders and initiate detailed product studies on the impact reduction potential that could be achieved by means of implementing product policy measures. Several ways of assessing product category environmental impacts and the effects of policy measures have been developed; 'bottom-up' or 'market-life-cycle assessment' is one of these, and we tried this approach for the situation in Belgium. Simplified life-cycle assessment (LCA) studies were conducted for representative average products within each function-based product category and the results were multiplied with market statistics. Using this approach, we found that building construction, building occupancy, and personal transport are among the major categories for Belgium. The major drawbacks of this approach are the system-level limitations and the existence of a broad spectrum of nonharmonized methods and datasets from which a sound preliminary selection had to be made. Consequently, the retrieval and selection of data was very time consuming and due to this we had to accept some major limitations in the study design. Nevertheless, the study has contributed to the development of a methodology for market-LCA and elements that can be picked up in currently ongoing and future work. The study concludes that to improve the feasibility and acceptance of this type of study there is a need for the development of a harmonized methodology on market-LCA, policy-relevant impact indicators as well as a harmonized and stakeholder-agreed-upon LCA databases.     

RAFT Nano-constructs: surfing to biological applications.

Biologically programmed molecular recognition provides the basis of all natural systems and supplies evolution-optimized functional materials from self-assembly of a limited number of molecular building blocks. Biomolecules such as peptides, nucleic acids and carbohydrates represent a diverse supply of structural building blocks for the chemist to design and fabricate new functional nanostructured architectures. In this context, we review here the chemistry we have developed to conjugate peptides with nucleic acids, carbohydrates, and organic molecules, as well as combinations thereof using a template-assembled approach. With this methodology, we have prepared new integrated functional systems exhibiting designed properties in the field of nanovectors, biosensors as well as controlled peptide self-assembly. Thus this molecular engineering approach allows for the rational design of systems with integrated tailor-made properties and paves the way to more elaborate applications by bottom-up design in the domain of nanobiosciences.     

Influence of the pH on (open) mixed culture fermentation of glucose: a chemostat study

Catabolic products from anaerobic fermentation processes are potentially of industrial interest. The volatile fatty acids and alcohols produced can be used as building blocks in chemical processes or applied directly as substrates in a mixed culture process to produce bioplastics. Development of such applications requires a predictable and controllable product spectrum of the fermentation process. The aim of the research described in this paper was (i) to investigate the product spectrum of an open mixed culture fermentation (MCF) process as a function of the pH, using glucose as substrate, and (ii) to relate the product spectrum obtained to generalized biochemical and thermodynamic considerations. A chemostat was operated under carbon and energy limitation in order to investigate the pH effect on the product spectrum in a MCF process. A transition from CO(2)/H(2) production at lower pH values to formate production at higher pH values was observed. The ratio of CO(2)/H(2) versus formate production was found to be related to the thermodynamics of formate dehydrogenation to CO(2)/H(2). This transition was associated with a shift in the catabolic products, from butyrate and acetate to ethanol and acetate, likely due to a decrease in the oxidation state of the electron carriers in the cell. The product spectrum of the MCF process as a function of the pH could largely be explained using general biochemical considerations.     

Biosynthesis of polyesters and polyamide building blocks using microbial fermentation and biotransformation

Biopolymers can be a green alternative to fossil-based polymers and can contribute to environmental protection because they are produced using renewable raw materials. Biopolymers are composed of various small subunits (building blocks) that are the intermediates or end products of major metabolic pathways. Most building blocks are secreted directly outside of cells, making downstream processes easier and more economic. These molecules can be extracted from fermentation broth and polymerized to produce a variety of biopolymers, e.g., polybutylene terephthalate, polyethylene terephthalate, polytrimethylene terephthalate, nylon-5,4 and nylon-4,6, with applications in medicine, pharmaceuticals, and textiles. Microbes are unable to naturally produce these types of polymers; thus, the production of building blocks and their polymerization is a fascinating approach for the production of these polymers. In comparison to naturally occurring biopolymers, synthesized polymers have improved and controlled structures and higher purity. The production of monomer units provides a new direction for polymer science because new classes of polymers with unique properties that were not previously possible can be prepared. Furthermore, the engineering of microbes for building-block production is an easy process compared to engineering an entire biopolymer synthesis pathway in a single microbe. Polyesters and polyamide polymers have become an important part of human life, and their demand is increasing daily. In this review, recent approaches and technology are discussed for the production of polyester/polyamide building blocks, i.e., 2-hydroxyisobutyric acid, 3-hydroxypropionic acid, mandelic acid, itaconic acid, adipic acid, terephthalic acid, succinic acid, 1,3-propanediol, 2,3-butanediol, 1,4-butanediol, 1,3-butanediol, cadaverine, and putrescine.     

A Process Chaining Approach toward Product Design for Environment

This article presents an approach toward product design for environment (DfE) at the level that integrates environmental hazard analysis with models of transformation processes. As a complementary analysis tool to life-cycle assessment (LCA), this method would support detailed design decisions through modeling of a "process chain" for a subset of the product's life cycle. The building blocks for this approach are a set of unit process models that can convert process and design parameters into estimates for energy utilization, production scrap, and ancillary waste flows. These values for quantity of environmental releases can be integrated using a multicriiteria environmental hazard evaluation methodology that can estimate the "qualrty" of environmental releases. Finally, the waste information can be used to support a design model that can link design parameters to material, process, and operational parameter selection. A case study illustrating printed circuit board (PCB) assembly is presented to show process chain implementation in manufacturing applications.     

Recombinant antibodies: towards a new generation of antivenoms?

Poisoning by scorpion venoms is a major health hazard in tropical and subtropical regions and serum therapy, which was discovered in 1894, remains the only specific treatment. No real progress has been made since this time and the therapeutic use of antivenoms which still consists in polyclonal antibody fragments from the sera of immunized animals may be associated with major drawbacks. Protein engineering now allows to design novel recombinant antibody fragments which are superior to polyclonal antivenoms in homogeneity, specific activity and possibly safety. Several single-chain antibody fragments (scFvs) which neutralize scorpion toxins have been produced and characterized over the last few years. These scFvs can also be used as building blocks to engineer more complex structures including multivalent monospecific antibody fragments (diabodies, triabodies) and bispecific molecules (tandem-scFv). Some of these molecules neutralize scorpion neurotoxins and protect mice from experimental envenoming. Thus, research projects currently underway suggest that new strategies might soon be available to treat poisonings in the absence of socio-economic considerations.     

Principles of nanostructure design with protein building blocks

Currently there is increasing interest in nanostructures and their design. Nanostructure design involves the ability to predictably manipulate the properties of the self-assembly of autonomous units. Autonomous units have preferred conformational states. The units can be synthetic material science-based or derived from functional biological macromolecules. Autonomous biological building blocks with available structures provide an extremely rich and useful resource for design. For proteins, the structural databases contain large libraries of protein molecules and their building blocks with a range of shapes, surfaces, and chemical properties. The introduction of engineered synthetic residues or short peptides into these can expand the available chemical space and enhance the desired properties. Here we focus on the principles of nanostructure design with protein building blocks.     

Combinatorial synthesis of natural products

Combinatorial syntheses allow production of compound libraries in an expeditious and organized manner immediately applicable for high-throughput screening. Natural products possess a pedigree to justify quality and appreciation in drug discovery and development. Currently, we are seeing a rapid increase in application of natural products in combinatorial chemistry and vice versa. The therapeutic areas of infectious disease and oncology still dominate but many new areas are emerging. Several complex natural products have now been synthesised by solid-phase methods and have created the foundation for preparation of combinatorial libraries. In other examples, natural products or intermediates have served as building blocks or scaffolds in the synthesis of complex natural products, bioactive analogues or designed hybrid molecules. Finally, structural motifs from the biologically active parent molecule have been identified and have served for design of natural product mimicry, which facilitates the creation of combinatorial libraries.     

Drug discovery beyond the 'rule-of-five'

Although a very useful guideline for orally bioavailable small-molecule drug design, the 'rule-of-five' (also known as 'Lipinski's rule of drug-likeness') has to some extent been overemphasized. Firstly, only 51% of all FDA-approved small-molecule drugs are both used orally and comply with the 'rule-of-five'. This does not even include the increasing number of biologicals of which several have reached 'blockbuster' status. Secondly, it does not cover natural product and semisynthetic natural product drugs, which constitute over one-third of all marketed small-molecule drugs. A more balanced and programmatic approach to drug discovery should be more productive than to rely on an overemphasis of 'rule-of-five' compliance. Rather it should consider proactively the development of parenteral drugs in parallel to oral drugs and to consider the development of therapeutic antibodies in parallel to small-molecule drugs. These are particularly relevant for efforts against 'first-in-class' and/or particularly challenging targets such as proteases and those involving protein-protein interactions. In addition, more effort should be invested in natural product research. Emerging novel technologies such as synthetic biology (genetic engineering of living organisms to produce small-molecule therapeutics) may address several challenging issues of natural product-based drug discovery including synthetic feasibility and ligand efficiency.     

Using anticipatory life cycle assessment to enable future sustainable construction

The built environment is the largest single emitter of CO₂ and an important consumer of energy. Much research has gone into the improved efficiency of building operation and construction products. Life Cycle Assessment (LCA) is commonly used to assess existing buildings or building products. Classic LCA, however, is not suited for evaluating the environmental performance of developing technologies. A new approach, anticipatory LCA (a‐LCA), promises various advantages and can be used as a design constraint during the product development stage. It helps overcome four challenges: (i) data availability, (ii) stakeholder inclusion, (iii) risk assessment, and (iv) multi‐criteria problems. This article's contribution to the line of research is twofold: first, it adapts the a‐LCA approach for construction‐specific purposes in theoretical terms for the four challenges. Second, it applies the method to an innovative prefabricated modular envelope system, the CleanTechBlock (CTB), focusing on challenge (i). Thirty‐six CTB designs are tested and compared to conventional walls. Inclusion of technology foresight is achieved through structured scenario analysis. Moreover, challenge (iv) is tackled through the analysis of different environmental impact categories, transport‐related impacts, and thickness of the wall assemblies of the CTB. The case study results show that optimized material choice and product design is needed to reach the lowest environmental impact. Methodological findings highlight the importance of context‐specific solutions and the need for benchmarking new products.     

The design and analysis of breeders' trials of sugar beet (Beta vulgaris) using two-dimensional blocking structures

A method for generating two-dimensional blocking designs to fit any shape and size of experimental area is presented. The method takes an alpha design appropriate to the experimental area and imposes additional blocking perpendicular to the alpha blocks. Improvements to the design are then made by repositioning entries within the alpha blocks. Although this method of construction is less sophisticated than for other two-dimensional designs, the designs are particularly suited to large scale breeders trials where no alternative two-dimensional design may exist. The designs have been used for 3 yr in a sugar beet breeding programme, and have given improvements in efficiency over one-dimensional alpha designs.     

Optimizing green design using ant colony-based approach

Purpose

In response to the increasing concerns on the environmental conservation and energy saving, manufacturers are more aware of proving the ‘green’ performance of their products. Some qualitative eco design tools are used to support the development of greener products; however, most of these tools require subjective judgement during the evaluation processes. This paper is therefore to propose an alternative approach that is objective, systematic and efficient, by integrating the ant colony optimization (ACO) and life cycle assessment (LCA), to facilitate the decision-making process.

Methods

The proposed integrative LCA-ACO approach aims to support the simultaneous thorough evaluations of multiple design options. A sequence of options of the lowest corresponding environmental impact value can be obtained. A case application example of various design combinations is presented to demonstrate the applicability of the proposed approach.

Results and discussion

The proposed approach offers decision makers a preliminary fast-track approach for screening decisions without lengthy processes of LCA studies. This approach helps the decision makers, especially during the early design selection stages, identifying the most appropriate design combination from the environmental perspective. The proposed approach is proved a significant contribution to the field of LCA and green product design.

Conclusions

Since full-scale LCA studies require significant effort in data collection processes and experts for result interpretations, it would be time consuming and costly to conduct a full-scale LCA during early product development processes. The proposed approach offers a more convenient way for decision makers to assess multiple design options regarding the environmental considerations. The case example presented in this paper proves the practicality of the proposed approach.

     

Exploiting mAb structure characteristics for a directed QbD implementation in early process development

In today’s biopharmaceutical industries, the lead time to develop and produce a new monoclonal antibody takes years before it can be launched commercially. The reasons lie in the complexity of the monoclonal antibodies and the need for high product quality to ensure clinical safety which has a significant impact on the process development time. Frameworks such as quality by design are becoming widely used by the pharmaceutical industries as they introduce a systematic approach for building quality into the product. However, full implementation of quality by design has still not been achieved due to attrition mainly from limited risk assessment of product properties as well as the large number of process factors affecting product quality that needs to be investigated during the process development. This has introduced a need for better methods and tools that can be used for early risk assessment and predictions of critical product properties and process factors to enhance process development and reduce costs. In this review, we investigate how the quantitative structure–activity relationships framework can be applied to an existing process development framework such as quality by design in order to increase product understanding based on the protein structure of monoclonal antibodies. Compared to quality by design, where the effect of process parameters on the drug product are explored, quantitative structure–activity relationships gives a reversed perspective which investigates how the protein structure can affect the performance in different unit operations. This provides valuable information that can be used during the early process development of new drug products where limited process understanding is available. Thus, quantitative structure–activity relationships methodology is explored and explained in detail and we investigate the means of directly linking the structural properties of monoclonal antibodies to process data. The resulting information as a decision tool can help to enhance the risk assessment to better aid process development and thereby overcome some of the limitations and challenges present in QbD implementation today.     

A novel complexity-to-diversity strategy for the diversity-oriented synthesis of structurally diverse and complex macrocycles from quinine

Recent years have witnessed a global decline in the productivity and advancement of the pharmaceutical industry. A major contributing factor to this is the downturn in drug discovery successes. This can be attributed to the lack of structural (particularly scaffold) diversity and structural complexity exhibited by current small molecule screening collections.Macrocycles have been shown to exhibit a diverse range of biological properties, with over 100 natural product-derived examples currently marketed as FDA-approved drugs. Despite this, synthetic macrocycles are widely considered to be a poorly explored structural class within drug discovery, which can be attributed to their synthetic intractability.Herein we describe a novel complexity-to-diversity strategy for the diversity-oriented synthesis of novel, structurally complex and diverse macrocyclic scaffolds from natural product starting materials. This approach exploits the inherent structural (including functional) and stereochemical complexity of natural products in order to rapidly generate diversity and complexity. Readily-accessible natural product-derived intermediates serve as structural templates which can be divergently functionalized with different building blocks to generate a diverse range of acyclic precursors. Subsequent macrocyclisation then furnishes compounds that are each based around a distinct molecular scaffold. Thus, high levels of library scaffold diversity can be rapidly achieved. In this proof-of-concept study, the natural product quinine was used as the foundation for library synthesis, and six novel structurally diverse, highly complex and functionalized macrocycles were generated.     

Capturing Nature's Diversity

Natural products are universally recognized to contribute valuable chemical diversity to the design of molecular screening libraries. The analysis undertaken in this work, provides a foundation for the generation of fragment screening libraries that capture the diverse range of molecular recognition building blocks embedded within natural products. Physicochemical properties were used to select fragment-sized natural products from a database of known natural products (Dictionary of Natural Products). PCA analysis was used to illustrate the positioning of the fragment subset within the property space of the non-fragment sized natural products in the dataset. Structural diversity was analysed by three distinct methods: atom function analysis, using pharmacophore fingerprints, atom type analysis, using radial fingerprints, and scaffold analysis. Small pharmacophore triplets, representing the range of chemical features present in natural products that are capable of engaging in molecular interactions with small, contiguous areas of protein binding surfaces, were analysed. We demonstrate that fragment-sized natural products capture more than half of the small pharmacophore triplet diversity observed in non fragment-sized natural product datasets. Atom type analysis using radial fingerprints was represented by a self-organizing map. We examined the structural diversity of non-flat fragment-sized natural product scaffolds, rich in sp3 configured centres. From these results we demonstrate that 2-ring fragment-sized natural products effectively balance the opposing characteristics of minimal complexity and broad structural diversity when compared to the larger, more complex fragment-like natural products. These naturally-derived fragments could be used as the starting point for the generation of a highly diverse library with the scope for further medicinal chemistry elaboration due to their minimal structural complexity. This study highlights the possibility to capture a high proportion of the individual molecular interaction motifs embedded within natural products using a fragment screening library spanning 422 structural clusters and comprised of approximately 2800 natural products.     

Plasmid Vectors and Molecular Building Blocks for the Development of Genetic Manipulation Tools for Trypanosoma cruzi

The post genomic era revealed the need for developing better performing, easier to use and more sophisticated genetic manipulation tools for the study of Trypanosoma cruzi, the etiological agent of Chagas disease. In this work a series of plasmids that allow genetic manipulation of this protozoan parasite were developed. First of all we focused on useful tools to establish selection strategies for different strains and which can be employed as expression vectors. On the other hand molecular building blocks in the form of diverse selectable markers, modifiable fluorescent protein and epitope-tag coding sequences were produced. Both types of modules were harboured in backbone molecules conceived to offer multiple construction and sub-cloning strategies. These can be used to confer new properties to already available genetic manipulation tools or as starting points for whole novel designs. The performance of each plasmid and building block was determined independently. For illustration purposes, some simple direct practical applications were conducted.     

Building-block selectivity of polyketide synthases

For the past decade, polyketide synthases have presented an exciting paradigm for the controlled manipulation of complex natural product structure. These multifunctional enzymes catalyze the biosynthesis of polyketide natural products by stepwise condensation and modification of metabolically derived building blocks. In particular, regioselective modification of polyketide structure is possible by alterations in either intracellular acyl-CoA pools or, more commonly, by manipulation of acyl transferases that act as the primary gatekeepers for building blocks.     

Cyclic oligomer design with de novo αβ‐proteins

We have previously shown that monomeric globular αβ‐proteins can be designed de novo with considerable control over topology, size, and shape. In this paper, we investigate the design of cyclic homo‐oligomers from these starting points. We experimented with both keeping the original monomer backbones fixed during the cyclic docking and design process, and allowing the backbone of the monomer to conform to that of adjacent subunits in the homo‐oligomer. The latter flexible backbone protocol generated designs with shape complementarity approaching that of native homo‐oligomers, but experimental characterization showed that the fixed backbone designs were more stable and less aggregation prone. Designed C2 oligomers with β‐strand backbone interactions were structurally confirmed through x‐ray crystallography and small‐angle X‐ray scattering (SAXS). In contrast, C3‐C5 designed homo‐oligomers with primarily nonpolar residues at interfaces all formed a range of oligomeric states. Taken together, our results suggest that for homo‐oligomers formed from globular building blocks, improved structural specificity will be better achieved using monomers with increased shape complementarity and with more polar interfaces.