Deconvolution of Combinatorial Libraries for Drug Discovery:  Experimental Comparison of Pooling Strategies

Wilson-Lingardo, Laura; Davis, Peter W.; Ecker, David J.; Hébert, Normand; Acevedo, Oscar L.; Sprankle, Kelly G.; Brennan, Thomas P.; Schwarcz, Leslie; Freier, Susan M.; Wyatt, Jacqueline R.

doi:10.1021/jm960169g

“…Pooled screening methods have been explored to identify enzyme inhibitors 9 and to look for synergistic anti-inflammatory compound pairs 10 although the latter study did not yield novel synergistic compound pairs. Here we develop a pooled screening method named MuSIC ( M ultiplex S creen for I nteracting C ompounds) to screen a large collection of diverse FDA-approved or clinically-tested compounds.…”

Section: Introductionmentioning

confidence: 99%

Systematic identification of synergistic drug pairs targeting HIV

Tan¹,

Hu²,

Luquette³

et al. 2012

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The systematic identification of effective drug combinations has been hindered by the unavailability of methods that can explore the large combinatorial search space of drug interactions. Here we present a multiplex screening method named MuSIC (Multiplex Screening for Interacting Compounds), which expedites the comprehensive assessment of pair-wise compound interactions. We examined ~500,000 drug pairs from 1000 FDA-approved or clinically tested drugs and identified drugs that synergize to inhibit HIV replication. Our analysis reveals an enrichment of anti-inflammatory drugs in drug combinations that synergize against HIV, indicating HIV benefits from inflammation that accompanies its infection. Multiple drug pairs identified in this study, including glucocorticoid and nitazoxanide, synergize by targeting different steps of the HIV life cycle. As inflammation accompanies HIV infection, our findings indicate that inhibiting inflammation could curb HIV propagation. MuSIC can be applied to a wide variety of disease-relevant screens to facilitate efficient identification of compound combinations.

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“…Although active compounds are identified without iterative synthesis using positional scanning, in comparison with iterative deconvolution there is an increased likelihood that the most potent compound(s) will not be identified [98], [99].…”

Section: Deconvolution By Positional Scanningmentioning

confidence: 99%

“…But the number of split and pool operations that would be required for library synthesis is rather high so that building block mixtures are used in several of the library synthesis steps in order to reduce the number of operations. A thorough examination of the theoretical and experimental aspects of iterative and positional scanning deconvolution has been published [98].…”

Section: Deconvolution By Positional Scanningmentioning

confidence: 99%

Combinatorial Chemistry

Tiebes

¹

,

Peters

²

2000

Ullmann's Encyclopedia of Industrial Chemistry

0

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The article contains sections titled: 1. Introduction 2. Concept of Combinatorial Chemistry 3. Methods and Techniques of Combinatorial Synthesis 3.1. Synthetic Strategies Towards Combinatorial Libraries 3.1.1. Split ‐ Pool Synthesis Towards Combinatorial Libraries 3.1.1.1. Techniques using Resin Beads 3.1.1.2. Tea‐Bag Method 3.1.2. Parallel Synthesis Towards Combinatorial Libraries 3.1.2.1. Reaction Apparatus using Resin Beads 3.1.2.2. Multipin Technique 3.1.2.3. Spatially Addressable Parallel Synthesis on Silica Wafer 3.1.3. Reagent Mixture Synthesis Towards Combinatorial Libraries 3.2. Synthetic Methodology for Organic Library Construction 3.2.1. Solid‐Phase Organic Synthesis 3.2.1.1. Solid Support, Linker, and Cleavage Strategies 3.2.1.2. Reaction Portfolio 3.2.2. Synthesis in Solution and Liquid‐Phase Synthesis 4. Characterization of Combinatorial Libraries 4.1. Analytical Characterization 4.2. Hit Identification in Combinatorial Libraries by High‐Throughput Screening 4.2.1. Strategies for Libraries of Compound Mixtures 4.2.1.1. On‐Bead Screening 4.2.1.2. Deconvolution 4.2.1.2.1. Iterative Deconvolution 4.2.1.2.2. Deconvolution by Positional Scanning 4.2.1.2.3. Deconvolution by Orthogonal Libraries 4.2.1.3. Encoding 4.2.1.4. Multiple Cleavable Linkers 4.2.2. Strategies for Libraries of Separate Single Compounds 4.2.3. Conclusion 5. Automation and Data Processing 5.1. Synthesis Automation and Data Processing 5.2. Automated Purification 6. Library Design and Diversity Assessment 6.1. Diversity Assessment for Selection of Building Blocks or Compound 6.2. Iterative Optimization Methods 7. Economic Aspects and Industrial Case Studies 8. Further Developments 8.1. Combinatorial Chemistry and Catalysis 8.2. Combinatorial Chemistry and Material Science

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“…Different pooling strategies have been experimentally compared using a library of 810 phosphate diester-linked peptide trimers. The results showed that random pooling, positional scanning, and iterative methods identified the same active compound [25]. But applying an artificial procedure where the best compound was hidden in a pool of least active compounds failed to identify the optimal trimer structure [25].…”

Section: Limitations Of Pooled Compound Screening Strategiesmentioning

confidence: 99%

“…The results showed that random pooling, positional scanning, and iterative methods identified the same active compound [25]. But applying an artificial procedure where the best compound was hidden in a pool of least active compounds failed to identify the optimal trimer structure [25]. This is the primary reason behind the drive to miniaturization and increased throughput.…”

Section: Limitations Of Pooled Compound Screening Strategiesmentioning

confidence: 99%

High‐Throughput Screening

Turner

¹

,

Sterrer

²

,

Wiesmüller

³

2000

Ullmann's Encyclopedia of Industrial Chemistry

0

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The article contains sections titled: 1. Introduction to Drug Discovery and Screening 1.1. A Rationale for new Methods in Drug Discovery 1.2. Sources of Compounds for High‐Throughput Screening 1.3. Demands on High‐Throughput Screening 2. Compounds 2.1. Novel Approaches to Generate Chemical Diversity 2.2. Microreactor Systems 2.3. Limitations of Pooled Compound Screening Strategies 3. Screening Technology 3.1. Chemistry, Biology, and Technology 3.2. Primary, Secondary, and Tertiary Screening 3.3. Miniaturization, Automation and Homogeneous Assays 3.4. Detection Technologies for High‐Throughput Screening 3.5. Examples of Specific Fluorescence Detection Technologies for High‐Throughput Screening 3.6. Case Study EVOscreen 4. Acknowledgements

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Deconvolution of Combinatorial Libraries for Drug Discovery: Experimental Comparison of Pooling Strategies

Cited by 66 publications

References 20 publications

Systematic identification of synergistic drug pairs targeting HIV

Systematic identification of synergistic drug pairs targeting HIV

Combinatorial Chemistry

High‐Throughput Screening

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