Discovery Of Drug Combinations Research Articles

Chapter 3 - Parallel Imaging Microfluidic Cytometer

By adding an additional degree of freedom from multichannel flow, the parallel microfluidic cytometer (PMC) combines some of the best features of fluorescence-activated flow cytometry (FCM) and microscope-based high-content screening (HCS). The PMC (i) lends itself to fast processing of large numbers of samples, (ii) adds a 1D imaging capability for intracellular localization assays (HCS), (iii) has a high rare-cell sensitivity, and (iv) has an unusual capability for time-synchronized sampling. An inability to practically handle large sample numbers has restricted applications of conventional flow cytometers and microscopes in combinatorial cell assays, network biology, and drug discovery. The PMC promises to relieve a bottleneck in these previously constrained applications. The PMC may also be a powerful tool for finding rare primary cells in the clinic. The multichannel architecture of current PMC prototypes allows 384 unique samples for a cell-based screen to be read out in ∼6-10 min, about 30 times the speed of most current FCM systems. In 1D intracellular imaging, the PMC can obtain protein localization using HCS marker strategies at many times for the sample throughput of charge-coupled device (CCD)-based microscopes or CCD-based single-channel flow cytometers. The PMC also permits the signal integration time to be varied over a larger range than is practical in conventional flow cytometers. The signal-to-noise advantages are useful, for example, in counting rare positive cells in the most difficult early stages of genome-wide screening. We review the status of parallel microfluidic cytometry and discuss some of the directions the new technology may take.

Boron‐Based Dipolar Multicomponent Reactions: Simple Generation of Substituted Aziridines, Oxazolidines and Pyrrolidines

New multicomponent reactions of aldehydes, isocyanides, trialkylboron reagents and dipolarophiles have been developed as an efficient route to diverse scaffolds, including aziridines, oxazolidines and poly-substituted pyrrolidines. This chemistry, inspired by a report by Hesse in 1965, is simple and involves mild conditions. Computational studies provide a basis to investigate the stereochemical features observed in the formation of oxazolidines and four-component adducts, and permit identification of potential factors that might influence the outcome of the multicomponent reaction. Thus, a rational screening of all the components and reaction parameters is made to examine the manifold mechanistic pathways and establish the practical limits for standard applications. Finally, intramolecular and solid-supported versions of these reactions bring new synthetic possibilities and practical protocols. Overall, the results describe a new family of multicomponent reactions valuable not only for organic reactivity, but also for combinatorial chemistry and drug discovery.

The contribution of (not so) public research to commercial innovations in the field of combinatorial chemistry

This paper examines the roles that publicly funded research play in the process of combinatorial drug discovery. It is shown that firms rely heavily on public research knowledge and, even more so, on education in organic chemistry, genomics and biochemistry. Publicly funded research also led to the creation of dozens of chemical-based companies, provided firms with an access to a larger network of innovators and generated important instruments and methods that are being used throughout the value chain of combinatorial drug discovery. The effects of public research, however, often look different depending on whether one sees them through the prism of larger or smaller firms, EU15 countries or the US, universities or other PROs.

Method Development for a Pyridobenzodiazepine Library with Multiple Diversification Points

ADVERTISEMENT RETURN TO ISSUEPREVReportNEXTMethod Development for a Pyridobenzodiazepine Library with Multiple Diversification PointsFuqiang Shi, Xianxiu Xu, Lianyou Zheng, Qun Dang, and Xu Bai*View Author Information The Center for Combinatorial Chemistry and Drug Discovery, Jilin University, 75 Haiwai Street, Changchun, Jilin 130012, P. R. China* To whom correspondence should be addressed. Tel: +86-431-85188955 . Fax: +86-431-85188900. E-mail: [email protected]Cite this: J. Comb. Chem. 2008, 10, 2, 158–161Publication Date (Web):February 9, 2008Publication History Received27 December 2007Published online9 February 2008Published inissue 1 March 2008https://doi.org/10.1021/cc7002039Copyright © 2008 American Chemical SocietyRIGHTS & PERMISSIONSArticle Views939Altmetric-Citations24LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit Read OnlinePDF (87 KB) Supporting Info (1)»Supporting Information Supporting Information SUBJECTS:Aromatic compounds,Cyclization,Organic acids,Pyridines,Solvents Get e-Alerts

A Scalable Approach to Combinatorial Library Design for Drug Discovery

In this paper, we propose an algorithm for the design of lead generation libraries required in combinatorial drug discovery. This algorithm addresses simultaneously the two key criteria of diversity and representativeness of compounds in the resulting library and is computationally efficient when applied to a large class of lead generation design problems. At the same time, additional constraints on experimental resources are also incorporated in the framework presented in this paper. A computationally efficient scalable algorithm is developed, where the ability of the deterministic annealing algorithm to identify clusters is exploited to truncate computations over the entire data set to computations over individual clusters. An analysis of this algorithm quantifies the tradeoff between the error due to truncation and computational effort. Results applied on test data sets corroborate the analysis and show improvement by factors as large as 10 or more, depending on the data sets.

Framework and practice of network-based studies for Chinese herbal formula

The ZHENG (syndrome of traditional Chinese medicine) oriented effects and the multiple-targets' mechanism are the main challenges encountered by recent researches for Chinese herbal formula. Using methods of bioinformatics and systems biology, we proposed a biological network-based framework for understanding the mechanism of Chinese herbal formula, and reviewed our studies under this framework which aimed to explore the relationship between Chinese herbal formula and corresponding ZHENGs, as well as the synergism of herbal combinations. These studies include the network construction for cold or heat ZHENG and its relationship with herbal formula of hot or cold nature, the biological network construction of angiogenesis, and the network regulation-based emergent property of an herbal combination with anti-angiogenesis synergism extracting from the cold formula. It is shown that the ZHENG-oriented effects and the herbal synergism can be nicely explicated by such network-based approaches. Thus, the network-based drug combination discovery, as well as the "traditional Chinese medicine bioinformatics (TCMB)" and "TCM computational systems biology" combining with computational and experimental approaches, is conceivable and can open a new avenue for understanding Chinese herbal formula.

Condition‐Directable Reaction: Regio‐ and Stereoselective Elimination of 2,3‐Dibromo‐2‐methylpropyl Phenyl Sulfone via Base‐solvent Selection

Diversity‐oriented organic synthesis is an important approach for combinatorial chemistry and drug discovery. An example of this approach is selective elimination of 2,3‐dibromo‐2‐methylpropyl phenyl sulfone 5 to potentially useful vinyl sulfones 6 E/Z and vinyl bromides 7 E/Z , which is achieved by choosing reaction conditions. This work was done during my graduate research under the guidance of Philip L. Fuchs in the Department of Chemistry at Purdue University, West Lafayette, Indiana, USA.

Novel Heterocyclic Scaffold Consisting of Indole-Fused Pteridines

ADVERTISEMENT RETURN TO ISSUEPREVReportNEXTNovel Heterocyclic Scaffold Consisting of Indole-Fused PteridinesLianyou Zheng, Jinbao Xiang, Qun Dang, Sigen Guo, and Xu BaiView Author Information The Center for Combinatorial Chemistry and Drug Discovery, Jilin University, 75 Jinlai Street, Changchun, Jilin 130012, P.R. China Cite this: J. Comb. Chem. 2005, 7, 6, 813–815Publication Date (Web):October 26, 2005Publication History Received25 June 2005Published online26 October 2005Published inissue 1 November 2005https://doi.org/10.1021/cc0500809Copyright © 2005 American Chemical SocietyRIGHTS & PERMISSIONSArticle Views668Altmetric-Citations29LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit Read OnlinePDF (53 KB) Supporting Info (1)»Supporting Information Supporting Information SUBJECTS:Aldehydes,Aromatic compounds,Cyclization,Indoles,Ketones Get e-Alerts

A General Technique To Rank Protein−Ligand Binding Affinities and Determine Allosteric versus Direct Binding Site Competition in Compound Mixtures

To realize the full potential of combinatorial chemistry-based drug discovery, generic and efficient tools must be developed that apply the strengths of diversity-oriented chemical synthesis to the identification and optimization of lead compounds for disease-associated protein targets. We report an affinity selection-mass spectrometry (AS-MS) method for protein-ligand affinity ranking and the classification of ligands by binding site. The method incorporates the following steps: (1) an affinity selection stage, where protein-binding compounds are selected from pools of ligands in the presence of varying concentrations of a competitor ligand, (2) a first chromatography stage to separate unbound ligands from protein-ligand complexes, and (3) a second chromatography stage to dissociate the ligands from the complexes for identification and quantification by MS. The ability of the competitor ligand to displace a target-bound library member, as measured by MS, reveals the binding site classification and affinity ranking of the mixture components. The technique requires no radiolabel incorporation or direct biochemical assay, no modification or immobilization of the compounds or target protein, and all reaction components, including any buffers or cofactors required for protein stability, are free in solution. We demonstrate the method for several compounds of wide structural variety against representatives of the most important protein classes in contemporary drug discovery, including novel ATP-competitive and allosteric inhibitors of the Akt-1 (PKB) and Zap-70 kinases, and previously undisclosed antagonists of the M(2) muscarinic acetylcholine receptor, a G-protein coupled receptor (GPCR). The theoretical basis of the technique is analyzed mathematically, allowing quantitative estimation of binding affinities and, in the case of allosteric interaction, absolute determination of binding cooperativity. The method is readily applicable to high-throughput screening hit triage, combinatorial library-based affinity optimization, and developing structure-activity relationships among multiple ligands to a given receptor.

Combinatorial synthesis in micro reactors.

This article reviews the current and future applications of micro reactors in the field of combinatorial chemistry and drug discovery. Liquid phase reactions have been used to illustrate the advantages of performing chemical reactions in micro reactors which illustrate that reactions can be performed very rapidly in high yield to enable the preparation of combinatorial libraries of structurally related compounds.

Is Phage Display Technology on Target for Developing Peptide-Based Cancer Drugs?

New tumor targeting agents are required to advance cancer diagnosis and treatment. Bacteriophage (phage) display technology, a molecular genetic means of combinatorial drug discovery, is an emerging approach to identify and improve peptide molecules as pharmaceuticals. Peptides are thought to have clinically desirable benefits over currently used biomolecules, such as antibodies, because of their rapid blood clearance, increased diffusion and tissue penetration, non-immunogenic nature and ease of synthesis. Using phage display, one can rapidly and simultaneously survey billion-clone peptide libraries, resulting in large numbers of "hits". However, only a few lead compounds resulting from the hits historically reach the drug market. Hence determining which peptide may best translate into a useful drug is of particular importance. Examination of successfully marketed drugs has highlighted key features of a winning agent, including low molecular weight, high affinity, stability, solubility, lipophilicity and conformational rigidity. Although peptide modulators of tumor cell function and cancer targeting agents have been developed, the majority of peptide-based drugs reported thus far are immune and cardiac regulators. In this review, we will highlight how phage display has been employed to isolate peptides that target key steps in cancer progression--from tumor growth to metastasis--and how phage display technology can be harnessed to select a priori peptides with inherent features essential for anti-cancer drug efficacy. In 2003, phage display provided us with several novel peptides not only in clinical trials but approved by the FDA for use as therapeutics in a variety of diseases--suggesting that the future looks bright for phage display in anti-cancer drug development.

Synthesis and application of functional peptides as cell nucleus-directed molecules in the treatment of malignant diseases.

The unique functions of biomolecules, including transport across biological membranes (e.g. the cell membrane, the nuclear envelope), modulation of protein function, gene transcription, reconstitution of the malignant transformation, and viral, bacterial and fungal activities underlie a high pharmaceutical potential. The development of combinatorial functional peptide modules in this important area has been slow, in contrast to the rapid development in the synthesis of small biopolymers. The conjugation of a short transmembrane transport peptide module with a cell nucleus address peptide module and with any substance is attractive for preparation of BioShuttle-based peptides because of the well-established automated synthesis of peptides. Variation of the different functional modules for drug targeting and the choice of substances can be combined to create novel bioconjugates with unique properties. This article provides an overview of previous work on the BioShuttle technology and outlines the promising use of this approach in combinatorial peptide synthesis and drug discovery.

Incorporation of unprotected heterocyclic side chains into peptoid oligomers via solid-phase submonomer synthesis.

Peptoids (N-substituted glycines) are an important class of biomimetic oligomers that have made a significant impact in the areas of combinatorial drug discovery, gene therapy, drug delivery, and biopolymer folding in recent years. Sequence-specific peptoid oligomers are easily assembled from primary amines by the solid-phase submonomer method. However, most amines that contain heterocyclic nitrogens in the side chain do not incorporate efficiently. We present here a straightforward revision of the submonomer method that allows efficient incorporation of unprotected imidazoles, pyridines, pyrazines, indoles, and quinolines into oligomers as long as 15 monomers in length. This improved method uses chloroacetic acid instead of bromoacetic acid in the acylation step of the monomer addition cycle, and allows for the incorporation of new side chains that should enable the synthesis of peptoids with entirely new properties.

Introducing Freshmen Students to the Practice of Solid-Phase Synthesis

Background and Rationale for the Experiment Solid-phase chemistry has revolutionized the synthesis of organic compounds, peptides, oligonucleotides, carbohydrates, drugs, and combinatorial libraries (1‐5). Although many types of compounds incorporating a variety of building blocks can be created, all solid-phase syntheses share a common approach. In a typical synthesis, starting material is anchored to a polymeric support and transformed into product by the action of solution-phase reagents. The product is then liberated into solution. The reverse approach has been used to convert solution-phase reactants into products by means of supportimmobilized reagents and catalysts (6 ). Solid-phase organic synthesis is effective because reagents can be used in excess to drive reactions and immobilized products can be purified by repeated washings (7). In addition, syntheses can be automated. By combining these attractive features, multistep syntheses that would be considered unfeasible under homogeneous solutionphase conditions have been realized. The merit and popularity of solid-phase protocols are illustrated by the example of Bruce Merrifield, who received a Nobel Prize for his seminal contribution, and further, by explosive developments in combinatorial chemistry and drug discovery (5, 8‐11). Our goal was to introduce students in the early stages of academic development to the principles and practice of synthesis. Freshmen students attending a “pick-a-project” course were ideal subjects for the study. Several enrollees had expressed a curiosity in the topic of synthetic chemistry, but clearly lacked the practical experience required to carry out a multistep solution synthesis. As solid-phase methods have proven advantageous, popular, relevant, and technically facile, a project focused on solid-phase synthesis showed promise as an instructional vehicle. Peptide synthesis in particular was chosen because its chemistry has been developed to the point where success is virtually guaranteed if protocols are followed faithfully (2, 12‐14). The novelty of presenting peptide chemistry to freshmen students in a tangible, hands-on fashion rather than by using a textbook approach was also a deciding factor (15). Structure, Content, and Pedagogy Students were asked to write a project proposal, present goals, rationale, and methods to a committee, implement the proposal, document results, and conclude the project in report and oral PowerPoint format before peers and faculty. In addition to instructor guidance and support, the students had intranet access to guidelines on preparing proposals, reports, and oral presentations and to mandatory readings on the subjects of synthesis and analysis (2, 12‐18). Basic chromatography, spectrometry, spectroscopy, kinetics, and enzyme function were discussed, and detailed protocols were supplied to facilitate in-lab instruction. Project objectives were realized by adopting a guided, step-by-step, hands-on approach. The students worked and studied collaboratively in order to promote interactive learning. They were introduced to key concepts with the aid of laboratory demonstrations and visual tools and were encouraged to consolidate these concepts as they implemented the project. The completed project was archived on the intranet for the benefit of future enrollees. Synthesis, Analysis, and Application

Strategies of biotechnology firms towards new, platform technologies

The human therapeutics sector of the biotechnology industry is the subject of a vast body of empirical literature, which attempts to analyse various success and failure factors for participating companies. This paper synthesises the historical trajectory of three current, leading-edge platform biotechnologies, namely the Polymerase Chain Reaction (PCR), combinatorial drug discovery, and gene therapy, and describes how these technical innovations have influenced the strategic choices that participating companies have made. The paper finds that a company with a unique proprietary position which can spawn a platform biotechnology can also create a virtual monopoly on the proliferation of that technology. If, on the other hand, the platform technology is created by proprietary contributions from several companies, then these companies tend to be very active in strategic alliances, and in the case of combinatorial drug discovery and gene therapy, this has resulted in the creation of four consortia.

Multistage Accurate Mass Spectrometry: A “Basket in a Basket” Approach for Structure Elucidation and Its Application to a Compound from Combinatorial Synthesis

A "basket in a basket" method based on a multistage accurate mass spectrometric (MAMS) technique was developed and demonstrated by obtaining a unique elemental composition of a compound (with a molecular weight of 517) from combinatorial synthesis. The accurate masses for the parent and the fragment ions were obtained with up to five stages of MAMS using Fourier transform ion cyclotron resonance mass spectrometry (FTICR-MS). This approach requires only input of elements used in the synthetic processes and some constraints about unusual light elements, such as fluorine, while the compositions of the parent ions and their fragments are obtained for structure elucidation. Conversely, accuracy of better than 0.02 ppm (assuming elements C, H, N, O, S, and F are involved) would be required in order to define a unique composition for the same mass using a direct accurate mass measurement because the number of possible elemental compositions increases sharply as the mass increases. Similarly, due to the uncertainty in determining elemental compositions of fragments and complexity of possible internal fragmentation, tandem mass spectrometry may not provide enough information for structure elucidation of unknown compounds, especially of the organic molecules in the mass range of 300-1000 Da, typically encountered in combinatorial lead generation. The application of MAMS to combinatorial drug discovery is particularly advantageous since the built-in chemical information from the synthesis can be used as constraints. The implementation of a nanoelectrospray ionization technique makes this approach practical for characterization of small quantities of compounds typically available from lead generation processes.

Solution Phase Combinatorial Chemistry. Synthesis of Novel Linear Pyridinopolyamine Libraries with Potent Antibacterial Activity

Novel linear pyridinopolyamine derivatives 1−3, 7, and 8 have been synthesized as scaffolds for combinatorial drug discovery. The mono-t-Boc- and monotosyl-protected linear scaffolds 1 and 2 were obtained by a Schiff base type cyclization of 2,6-pyridinedicarboxaldehyde (24) with monoprotected triamines 22 and 23 using Ni2+ as a metal template, followed by reductive cleavage and decomplexation in a one-pot procedure. The unprotected linear scaffold 3 was obtained by treating 1 with TFA. Scaffold 1 was also synthesized from the orthogonally protected pyridinopolyamine 7 which was constructed from 2,6-bis(bromomethyl)pyridine (29) in four steps. Selective deprotection of the key intermediate 7 afforded 8, which was further selectively deprotected to give scaffold 1. A combinatorial chemistry strategy involving solution phase simultaneous addition of functionalities (SPSAF) is described. Thirteen high-purity tertiary amine libraries (9−21) (total 1638 compounds) were synthesized by the SPSAF and fix last methodologies from linear polyamine scaffolds 1 and 2. All libraries were examined by TLC, purified by chromatographic techniques, and characterized by 1H NMR and ESI MS spectral data. A fix last methodology was utilized to minimize chemical reactions and perform SAR studies directly on libraries. Several first-round sublibraries of scaffold 1, containing 126 compounds each, exhibited potent antibacterial activity with MICs of 1−12 μM against Streptococcus pyogenes and Escherichia coli imp-.

Combinatorial drug discovery: which methods will produce the greatest value?

Combinatorial strategies are important new approaches to drug discovery, and it seems quite likely that they will result in the discovery of interesting potential pharmaceuticals. However, it is less clear whether combinatorial approaches will result in quantum advances in therapeutics. Nor is there general agreement about the factors most important in defining how combinatorial strategies will provide value to the discovery of lead and therapeutic compounds. In this review, we propose criteria that define the value of combinatorial strategies and categorize the various approaches by: (a) the type of chemical space to be searched, (b) the tactics employed to synthesize and screen libraries, and (c) the structures of individual molecules in libraries. We evaluate the strengths and weaknesses of the various strategies and suggest milestones that can help to track their success.