High-throughput screening is an important component of the drug discovery process. The screening of libraries containing hundreds of thousands of compounds requires assays amenable to miniaturisation ...and automization. Combinatorial chemistry holds a unique promise to deliver structurally diverse libraries for early drug discovery. Among the various library forms, the one-bead-one-compound (OBOC) library, where each bead carries many copies of a single compound, holds the greatest potential for the rapid identification of novel hits against emerging drug targets. However, this potential has not yet been fully realized due to a number of technical obstacles. In this feature article, we review the progress that has been made in bead-based library screening and its application to the discovery of bioactive compounds. We identify the key challenges of this approach and highlight key steps needed for making a greater impact in the field.
High-throughput screening is an important component of the drug discovery process.
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.
Rational materials design based on prior knowledge is attractive because it promises to avoid time-consuming synthesis and testing of numerous materials candidates. However with the increase of ...complexity of materials, the scientific ability for the rational materials design becomes progressively limited. As a result of this complexity, combinatorial and high-throughput (CHT) experimentation in materials science has been recognized as a new scientific approach to generate new knowledge. This review demonstrates the broad applicability of CHT experimentation technologies in discovery and optimization of new materials. We discuss general principles of CHT materials screening, followed by the detailed discussion of high-throughput materials characterization approaches, advances in data analysis/mining, and new materials developments facilitated by CHT experimentation. We critically analyze results of materials development in the areas most impacted by the CHT approaches, such as catalysis, electronic and functional materials, polymer-based industrial coatings, sensing materials, and biomaterials.
The formation of oximes and hydrazones is employed in numerous scientific fields as a simple and versatile conjugation strategy. This imine-forming reaction is applied in fields as diverse as polymer ...chemistry, biomaterials and hydrogels, dynamic combinatorial chemistry, organic synthesis, and chemical biology. Here we outline chemical developments in this field, with special focus on the past ∼10 years of developments. Recent strategies for installing reactive carbonyl groups and α-nucleophiles into biomolecules are described. The basic chemical properties of reactants and products in this reaction are then reviewed, with an eye to understanding the reaction’s mechanism and how reactant structure controls rates and equilibria in the process. Recent work that has uncovered structural features and new mechanisms for speeding the reaction, sometimes by orders of magnitude, is discussed. We describe recent studies that have identified especially fast reacting aldehyde/ketone substrates and structural effects that lead to rapid-reacting α-nucleophiles as well. Among the most effective new strategies has been the development of substituents near the reactive aldehyde group that either transfer protons at the transition state or trap the initially formed tetrahedral intermediates. In addition, the recent development of efficient nucleophilic catalysts for the reaction is outlined, improving greatly upon aniline, the classical catalyst for imine formation. A number of uses of such second- and third-generation catalysts in bioconjugation and in cellular applications are highlighted. While formation of hydrazone and oxime has been traditionally regarded as being limited by slow rates, developments in the past 5 years have resulted in completely overturning this limitation; indeed, the reaction is now one of the fastest and most versatile reactions available for conjugations of biomolecules and biomaterials.
This review is an updated and expanded version of the three prior reviews that were published in this journal in 1997, 2003, and 2007. In the case of all approved therapeutic agents, the time frame ...has been extended to cover the 30 years from January 1, 1981, to December 31, 2010, for all diseases worldwide, and from 1950 (earliest so far identified) to December 2010 for all approved antitumor drugs worldwide. We have continued to utilize our secondary subdivision of a “natural product mimic” or “NM” to join the original primary divisions and have added a new designation, “natural product botanical” or “NB”, to cover those botanical “defined mixtures” that have now been recognized as drug entities by the FDA and similar organizations. From the data presented, the utility of natural products as sources of novel structures, but not necessarily the final drug entity, is still alive and well. Thus, in the area of cancer, over the time frame from around the 1940s to date, of the 175 small molecules, 131, or 74.8%, are other than “S” (synthetic), with 85, or 48.6%, actually being either natural products or directly derived therefrom. In other areas, the influence of natural product structures is quite marked, with, as expected from prior information, the anti-infective area being dependent on natural products and their structures. Although combinatorial chemistry techniques have succeeded as methods of optimizing structures and have been used very successfully in the optimization of many recently approved agents, we are able to identify only one de novo combinatorial compound approved as a drug in this 30-year time frame. We wish to draw the attention of readers to the rapidly evolving recognition that a significant number of natural product drugs/leads are actually produced by microbes and/or microbial interactions with the “host from whence it was isolated”, and therefore we consider that this area of natural product research should be expanded significantly.
Since the decoding of the human genome, the quest to obtain more and more molecular information from smaller and smaller samples is intensifying. Today the burden of this challenge is being borne by ...planar arrays, but the quality of the data provided by this approach is limited by variations in performance between different arrays. Suspension arrays of encoded microspheres provide higher quality data, but the amount of molecular information that can be acquired with them is limited by the number of codes that can be distinguished in the same sample. New methods of preparing encoded particles promise to alleviate this problem, but in the face of a growing number of new technologies it is sometimes difficult to decide which, if any, will succeed. Herein we appraise these new forms of encoded particle critically, and ask if they can deliver the necessary multiplexing power and whether they will perform well in multiplexed assays.
Faster, smaller, more sensitive: Since the decoding of the human genome a defining trait has been the quest to obtain more and more molecular information from smaller and smaller samples. Latex microspheres encoded with fluorescent dyes allow dozens of molecules to be detected in the same sample at the same time, but the race is now on to develop new types of encoded particle that can extract even more information.
Acylhydrazone‐based (macro)molecules display an increasingly broad spectrum of applications, from small therapeutic molecules and metal‐ions probes to self‐healing films and biorelevant dynamic ...polymers. The acylhydrazone function is indeed of prime interest since its unique design combines hydrogen bonds, pH‐dependent reversibility, ability to undergo molecular exchanges, and a possible polyvalency. However, a key parameter of its use in aqueous media is the associated water‐solubility of the resulting (macro)molecule. This property can indeed become a limitation for applications requiring high concentrations or no organic cosolvent. This review first focuses on describing the acylhydrazone function, its properties, and its relevancy in dynamic combinatorial chemistry. Then it details the synthesis strategies (molecular design, cosolvent, reaction conditions) reported in the literature to ensure a sufficient solubilization of both single‐bond and multiple‐bond acylhydrazone (macro)molecules, together with their various applications.
Water‐soluble acylhydrazone‐based (macro)molecules display several properties of prime interest, and an increasingly broad spectrum of applications. However, their poor water‐solubility can be a limiting key parameter for their further use in aqueous media. In this context, this review describes different strategies employed in the literature to ensure a sufficient solubility in water, for single‐bond to multiple‐bond acylhydrazone (macro)molecules, including polyacylhydrazones.
DNA‐encoded chemical libraries (DECLs) are pools of DNA‐tagged small molecules that enable facile screening and identification of bio‐macromolecule binders. The successful development of DECLs has ...led to their increasingly important role in drug development, and screening hits have entered clinical trials. In this review, we summarize the development and currently active research areas of DECLs with a focus on contributions from groups at academic institutes. We further look at opportunities and future directions of DECL research in medicinal chemistry and chemical biology based on the symbiotic relationship between academia and industry. Challenges associated with the application of DECLs in academic drug discovery are further discussed.
Discovery with DECLs: Encoding with DNA sequence barcodes enables rapid and inexpensive synthesis and interrogation of compound libraries of unprecedented size. Screening DNA‐encoded chemical libraries (DECLs) is increasingly used in drug discovery, with applications in chemical biology under development. This minireview summarizes key achievements in the field and analyzes its challenges and opportunities.
Electrostatic and charge‐transfer contributions to CH–π complexes can be modulated by attaching electron‐withdrawing substituents to the carbon atom. While clearly stabilizing in the gas phase, the ...outcome of this chemical modification in water is more difficult to predict. Herein we provide a definitive and quantitative answer to this question employing a simple strategy based on dynamic combinatorial chemistry.
Electrostatic and charge‐transfer contributions to CH–π complexes can be modulated by attaching electron‐withdrawing substituents to the carbon atom. Although they have a clearly stabilizing effect in the gas phase, the influence of this chemical modification for the behavior in water is more difficult to predict. Dynamic combinatorial chemistry is used to provide a definitive and quantitative answer to this question.
The protein catalyzed capture agent (PCC) method is a powerful combinatorial screening strategy for discovering synthetic macrocyclic peptide ligands, called PCCs, to designated protein epitopes. The ...foundational concept of the PCC method is the use of in situ click chemistry to survey large combinatorial libraries of peptides for ligands to designated biological targets. State-of-the-art PCC screens integrate synthetic libraries of constrained macrocyclic peptides with epitope-specific targeting strategies to identify high-affinity (<100 nM) binders de novo. Automated instrumentation can accelerate PCC discovery to a rapid 2-week timeframe. Here, we describe methods to perform combinatorial screens that yield epitope-targeted PCCs.
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