Targeted molecular imaging techniques have become indispensable tools in modern diagnostics because they provide accurate and specific diagnosis of disease information. Conventional nonspecific ...contrast agents suffer from low targeting efficiency; thus, the use of molecularly targeted imaging probes is needed depending on different imaging modalities. Although recent technologies have yielded various strategies for designing smart probes, utilization of peptide-based probes has been most successful. Phage display technology and combinatorial peptide chemistry have profoundly impacted the pool of available targeting peptides for the efficient and specific delivery of imaging labels. To date, selected peptides that target a variety of disease-related receptors and biomarkers are in place. These targeting peptides can be coupled with the appropriate imaging moieties or nanoplatforms on demand with the help of sophisticated bioconjugation or radiolabeling techniques. This review article examines the current trends in peptide-based imaging probes developed for in vivo applications. We discuss the advantage of and challenges in developing peptide-based probes and summarize current systems with respect to their unique design strategies and applications.
•Advances in the combination of the CuAAC reaction with direct screening.•Before library assembly, the bioisosteric potential of 1,2,3-triazole should be confirmed.•The degree of diversity and ...drug-like properties are important to a 1,2,3-triazole library.•The potential undesirable influence of the crude samples in bioassay should be considered.•Other robust reactions suitable for rapid synthesis of diverse libraries will be exploited.
The rapid assembly and in situ screening of focused combinatorial fragment libraries using CuAAC click chemistry is a highly robust and efficient strategy for establishing SAR and for discovering bioactive molecules. This review outlines the current status of this methodology in drug discovery application. The inherent limitations, challenges and prospects are critically discussed.
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The final step of lignin biosynthesis is the polymerization of monolignols in apoplastic cell wall domains. In this process, monolignols secreted by lignifying cells, or occasionally ...neighboring non-lignifying and/or other lignifying cells, are activated by cell-wall-localized oxidation systems, such as laccase/O2 and/or peroxidase/H2O2, for combinatorial radical coupling to make the final lignin polymers. Plants can precisely control when, where, and which types of lignin polymers are assembled at tissue and cellular levels, but do not control the polymers’ exact chemical structures per se. Recent studies have begun to identify specific laccase and peroxidase proteins responsible for lignin polymerization in specific cell types and during different developmental stages. The coordination of polymerization machinery localization and monolignol supply is likely critical for the spatio-temporal patterning of lignin polymerization. Further advancement in this research area will continue to increase our capacity to manipulate lignin content/structure in biomass to meet our own biotechnological purposes.
Structure-based virtual ligand screening is emerging as a key paradigm for early drug discovery owing to the availability of high-resolution target structures
and ultra-large libraries of virtual ...compounds
. However, to keep pace with the rapid growth of virtual libraries, such as readily available for synthesis (REAL) combinatorial libraries
, new approaches to compound screening are needed
. Here we introduce a modular synthon-based approach-V-SYNTHES-to perform hierarchical structure-based screening of a REAL Space library of more than 11 billion compounds. V-SYNTHES first identifies the best scaffold-synthon combinations as seeds suitable for further growth, and then iteratively elaborates these seeds to select complete molecules with the best docking scores. This hierarchical combinatorial approach enables the rapid detection of the best-scoring compounds in the gigascale chemical space while performing docking of only a small fraction (<0.1%) of the library compounds. Chemical synthesis and experimental testing of novel cannabinoid antagonists predicted by V-SYNTHES demonstrated a 33% hit rate, including 14 submicromolar ligands, substantially improving over a standard virtual screening of the Enamine REAL diversity subset, which required approximately 100 times more computational resources. Synthesis of selected analogues of the best hits further improved potencies and affinities (best inhibitory constant (K
) = 0.9 nM) and CB
/CB
selectivity (50-200-fold). V-SYNTHES was also tested on a kinase target, ROCK1, further supporting its use for lead discovery. The approach is easily scalable for the rapid growth of combinatorial libraries and potentially adaptable to any docking algorithm.
There is considerable interest in the development of libraries of non‐peptidic macrocycles as a source of ligands for difficult targets. We report here the solid‐phase synthesis of a DNA‐encoded ...library of several hundred thousand thioether‐linked macrocycles. The library was designed to be highly diverse with respect to backbone scaffold diversity and to minimize the number of amide N−H bonds, which compromise cell permeability. The utility of the library as a source of protein ligands is demonstrated through the isolation of compounds that bind Streptavidin, a model target, with high affinity.
The discovery of ligands for the “undruggable proteome” is likely to require the development of new chemical matter with a greater “molecular wingspan” than traditional Lipinski‐compliant small molecules. A DNA‐encoded library (DEL) of non‐peptidic thioether macrocycles has been constructed and screened for high affinity protein ligands to a model protein, SA.
Although fire is now rarely used in synthetic chemistry, it was not until Robert Bunsen invented the burner in 1855 that the energy from this heat source could be applied to a reaction vessel in a ...focused manner. The Bunsen burner was later superseded by the isomantle, oil bath, or hot plate as a source for applying heat to a chemical reaction. In the past few years, heating and driving chemical reactions by microwave energy has been an increasingly popular theme in the scientific community. This nonclassical heating technique is slowly moving from a laboratory curiosity to an established technique that is heavily used in both academia and industry. The efficiency of “microwave flash heating” in dramatically reducing reaction times (from days and hours to minutes and seconds) is just one of the many advantages. This Review highlights recent applications of controlled microwave heating in modern organic synthesis, and discusses some of the underlying phenomena and issues involved.
Out of the kitchen into the laboratory: Direct heating by microwave irradiation (see picture) in many cases enables synthesis to be carried out in a fraction of the time required with conventional heating techniques. The use of microwave heating in organic synthesis is growing rapidly and the advantages not only include faster reaction times, but also higher product yields, cleaner reactions, better controllability, and reproducibility.
Target‐directed dynamic combinatorial chemistry (DCC) is an emerging technique for the efficient identification of inhibitors of pharmacologically relevant targets. In this contribution, we present ...an application for a bacterial target, the lectin FimH, a crucial virulence factor of uropathogenic E. coli being the main cause of urinary tract infections. A small dynamic library of acylhydrazones was formed from aldehydes and hydrazides and equilibrated at neutral pH in presence of aniline as nucleophilic catalyst. The major success factors turned out to be an accordingly adjusted ratio of scaffolds and fragments, an adequate sample preparation prior to HPLC analysis, and the data processing. Only then did the ranking of the dynamic library constituents correlate well with affinity data. Furthermore, as a support of DCC applications especially to larger libraries, a new protocol for improved hit identification was established.
Right on target: A target‐directed dynamic combinatorial chemistry approach based on reversible acylhydrazones allowed the identification of high‐affinity ligands for a bacterial adhesin. The ratio of building blocks, sample preparation before HPLC analysis, and data procession has proven to be essential for success. Furthermore, removal of unbound ligands before analysis greatly contributed to the identification of good binders.
By the reaction of furan-2-carboxylic acids and furfural with diazonium salts 1a-j the arylfuran-2-carboxylic acids 4a-e and 5-arylfuran-2-carbaldehydes 5a-f were synthesized. Acids 4a-e were ...transformed into appropriated acylchlorides 6a-e and were used for preparation of 4-(5-aryl-2-furoyl)morpholines 7a-e. 4-(5-Aryl-2-furyl)carbonothioylmorpholines 8a-f were prepared from aldehydes 5a-f by using Willgerodt-Kindler reaction. The structures of the obtained compounds were confirmed by sup.1H NMR spectroscopy and elemental analysis. All these new compounds gave spectroscopic data in accordance with the proposed structures. The antimicrobial activities of synthesized compounds 7a-e and 8a-f were investigated and the compounds with high activity against C. neoformans ATCC 208821 were identified. Keywords: antimicrobial activity, 4-(5-aryl-2-furoyl)morpholines, 4-(5-aryl-2-furyl)carbonothioylmorpholines
An efficient strategy for the synthesis of large libraries of conformationally defined peptides is reported, using dynamic combinatorial chemistry as a tool to graft amino acid side chains on a ...well‐ordered 3D (3‐dimension) peptide backbone. Combining rationally designed scaffolds with combinatorial side chains selection represents an alternative method to access peptide libraries for structures that are not genetically encodable. This method would allow a breakthrough for the discovery of protein mimetic for unconventional targets for which little is known.
An efficient access to large libraries of conformationally defined peptides is reported, using dynamic combinatorial chemistry as a tool to graft amino acid's side‐chains in defined arrangement on a well‐ordered 3D peptide scaffold. We report here the design of a chemical system that ensures the scrambling of side‐chains on a pre‐organized scaffold leading to an isoenergetic library useful for ligand screening.
Artificial intelligence and various types of machine learning are of increasing interest not only in the natural sciences but also in a wide range of applied and engineering sciences. In this study, ...we rethink the view on combinatorial heterogeneous catalysis and combine machine learning methods with combinatorial approaches in electrocatalysis. Several machine learning methods were used to forecast water oxidation catalysts on the basis of literature published data sets and data from our own work. The machine learning models exhibit a decent prediction precision based on the data sets available and confirm that even simple models are suitable for good forecasts.
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