稀土掺杂上转换纳米颗粒-金属有机骨架复合材料的研究进展

稀土掺杂上转换纳米颗粒-金属有机骨架复合材料是一类新型的功能复合材料. 它不仅结合了稀土掺杂上转换纳米颗粒和金属有机骨架这两种材料的特性, 体现了两者复合后的协同效应, 还具有设计灵活和功能易拓展等优势. 本文聚焦稀土掺杂上转换纳米颗粒-金属有机框架复合材料的最新发展, 总结了该类复合材料的制备方法, 介绍了其在生物和催化等领域的应用, 并对其面临的挑战和发展前景进行了展望.     

Modular synthesis and preliminary biological evaluation of stereochemically diverse 1,3-dioxanes

Modular synthesis and substrate stereocontrol were combined to furnish 18,000 diverse 1,3-dioxanes whose distribution in chemical space rivals that of a reference set of over 2,000 bioactive small molecules. Library quality was assessed at key synthetic stages, culminating in a detailed postsynthesis analysis of purity, yield, and structural characterizability, and the resynthesis of library subsets that did not meet quality standards. The importance of this analysis-resynthesis process is highlighted by the discovery of new biological probes through organismal and protein binding assays, and by determination of the building block and stereochemical basis for their bioactivity. This evaluation of a portion of the 1,3-dioxane library suggests that many additional probes for chemical genetics will be identified as the entire library becomes biologically annotated.     

Emerging Methods and Design Principles for Cell‐Penetrant Peptides

Biomolecules such as antibodies, proteins, and peptides are important tools for chemical biology and leads for drug development. They have been used to inhibit a variety of extracellular proteins, but accessing intracellular proteins has been much more challenging. In this review, we discuss diverse chemical approaches that have yielded cell‐penetrant peptides and identify three distinct strategies: masking backbone amides, guanidinium group patterning, and amphipathic patterning. We summarize a growing number of large data sets, which are starting to reveal more specific design guidelines for each strategy. We also discuss advantages and disadvantages of current methods for quantifying cell penetration. Finally, we provide an overview of best‐odds approaches for applying these new methods and design principles to optimize cytosolic penetration for a given bioactive peptide.     

Designing compound subsets: comparison of random and rational approaches using statistical simulation

Compound subsets, which may be screened where it is not feasible or desirable to screen all available compounds, may be designed using rational or random selection. Literature on the relative performance of random versus rational selection reports conflicting observations, possibly because some random subsets might be more representative than others and perform better than subsets designed by rational means, or vice versa. In order to address this likelihood, we simulated a large number of rationally designed subsets for evaluation against an equally large number of randomly generated subsets. We found that our rationally designed subsets give higher mean hit rates compared to those of the random ones. We also compared subsets comprising random plates with subsets of random compounds and found that, while the mean hit rate of both is the same, the former demonstrates more variation in the hit rate. The choice of compound file, rational subset method, and ratio of the subset size to the compound file size are key factors in the relative performance of random and rational selection, and statistical simulation is a viable way to identify the selection approach appropriate for a subset.     

Biological mechanism profiling using an annotated compound library

We present a method for testing many biological mechanisms in cellular assays using an annotated library of 2036 small organic molecules. This annotated compound library represents a large-scale collection of compounds with diverse, experimentally confirmed biological mechanisms and effects. We found that this chemical library is (1) more structurally diverse than conventional, commercially available libraries, (2) enriched in active compounds in a tumor cell viability assay, and (3) capable of generating hypotheses regarding biological mechanisms underlying cellular processes. We elucidated biological mechanisms relevant to the antiproliferative activity of 85 compounds from this library that were selected using a high-throughput cell viability screen. We developed a novel automated scoring system for identifying statistically enriched mechanisms among such a subset of compounds. This scoring system can identify both previously known and potentially novel antiproliferative mechanisms.     

De novo design by pharmacophore-based searches in fragment spaces

De novo ligand design supports the search for novel molecular scaffolds in medicinal chemistry projects. This search can either be based on structural information of the targeted active site (structure-based approach) or on similarity to known binders (ligand-based approach). In the absence of structural information on the target, pharmacophores provide a way to find topologically novel scaffolds. Fragment spaces have proven to be a valuable source for molecular structures in de novo design that are both diverse and synthetically accessible. They also offer a simple way to formulate custom chemical spaces. We have implemented a new method which stochastically constructs new molecules from fragment spaces under consideration of a three dimensional pharmacophore. The program has been tested on several published pharmacophores and is shown to be able to reproduce scaffold hops from the literature, which resulted in new chemical entities.     

Lessons for fragment library design: analysis of output from multiple screening campaigns

Over the past 8 years, we have developed, refined and applied a fragment based discovery approach to a range of protein targets. Here we report computational analyses of various aspects of our fragment library and the results obtained for fragment screening. We reinforce the finding of others that the experimentally observed hit rate for screening fragments can be related to a computationally defined druggability index for the target. In general, the physicochemical properties of the fragment hits display the same profile as the library, as is expected for a truly diverse library which probes the relevant chemical space. An analysis of the fragment hits against various protein classes has shown that the physicochemical properties of the fragments are complementary to the properties of the target binding site. The effectiveness of some fragments appears to be achieved by an appropriate mix of pharmacophore features and enhanced aromaticity, with hydrophobic interactions playing an important role. The analysis emphasizes that it is possible to identify small fragments that are specific for different binding sites. To conclude, we discuss how the results could inform further development and improvement of our fragment library. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Identification of hits and lead structure candidates with limited resources by adaptive optimization

Three stochastic optimization algorithms (Simulated Annealing (SA), Evolution Strategy (ES), and Particle Swarm Optimization (PSO)) and a Random Search were assessed for their ability to generate small activity-enriched subsets of molecular compound libraries. The optimization algorithms were employed to perform an "intelligent" iterative sampling of library molecules avoiding the biological testing of the full library. This study was performed to find a suitable optimization algorithm along with suitable parametrization. Particularly, the optimal number of iterations and population size were of interest. Optimizations were performed with limited resources as the maximal number of compound evaluations was restricted to 300. Results show that all three optimization algorithms are able to produce comparably good results, clearly outperforming a Random Search. While ES was able to come up with good solutions after a few optimization cycles, SA favored high numbers of iterations and was therefore less suited for library design. We introduce PSOs as an alternative approach to focused library design. PSO was able to produce high quality solutions while exhibiting marked autoadaptivity. Its implicit step size control makes it a straightforward out-of-the-box optimization algorithm. We further demonstrate that a nearest neighbor algorithm can successfully be applied to map from continuous search space to discrete chemical space.     

A one-bead, one-stock solution approach to chemical genetics: part 2

BACKGROUND: Chemical genetics provides a systematic means to study biology using small molecules to effect spatial and temporal control over protein function. As complementary approaches, phenotypic and proteomic screens of structurally diverse and complex small molecules may yield not only interesting individual probes of biological function, but also global information about small molecule collections and the interactions of their members with biological systems. RESULTS: We report a general high-throughput method for converting high-capacity beads into arrayed stock solutions amenable to both phenotypic and proteomic assays. Polystyrene beads from diversity-oriented syntheses were arrayed individually into wells. Bound compounds were cleaved, eluted, and resuspended to generate 'mother plates' of stock solutions. The second phase of development of our technology platform includes optimized cleavage and elution conditions, a novel bead arraying method, and robotic distribution of stock solutions of small molecules into 'daughter plates' for direct use in chemical genetic assays. This library formatting strategy enables what we refer to as annotation screening, in which every member of a library is annotated with biological assay data. This phase was validated by arraying and screening 708 members of an encoded 4320-member library of structurally diverse and complex dihydropyrancarboxamides. CONCLUSIONS: Our 'one-bead, multiple-stock solution' library formatting strategy is a central element of a technology platform aimed at advancing chemical genetics. Annotation screening provides a means for biology to inform chemistry, complementary to the way that chemistry can inform biology in conventional ('investigator-initiated') small molecule screens.     

Current progress in natural product-like libraries for discovery screening

Natural product-like libraries represent an effort to combine the attractive features of natural products and combinatorial libraries for high-throughput screening. Three approaches to natural product-like library design are discussed: (1) Libraries based on core scaffolds from individual natural products, (2) libraries of diverse structures with general structural characteristics of natural products, and (3) libraries of diverse structures based on specific structural motifs from classes of natural products. Examples of successful applications in discovery screening are described for each category. These studies highlight the exciting potential of natural product-like libraries in both chemical biology and drug discovery.