Skip to main content
SpringerLink
Log in

High-Throughput Synthesis of Diverse Compound Collections for Lead Discovery and Optimization

  • Chapter
New Approaches to Drug Discovery

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 232))

Abstract

Small-molecule intervention of protein function is one central dogma of drug discovery. The generation of small-molecule libraries fuels the discovery pipeline at many stages and thereby resembles a key aspect of this endeavor. High-throughput synthesis is a major source for compound libraries utilized in academia and industry, seeking new chemical modulators of pharmacological targets. Here, we discuss the crucial factors of library design strategies from the perspective of synthetic chemistry, giving a brief historic background and a summary of current approaches. Simple measures of success of a high-throughput synthesis such as quantity or diversity have long been discarded and replaced by more integrated measures. Case studies are presented and put into context to highlight the cross-connectivity of the various stages of the drug discovery process.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Abbreviations

ADMET:

Absorption, distribution, metabolism, excretion, and toxicity

BIOS:

Biology-oriented synthesis

DCR:

Divide, couple, and recombine

DEL:

DNA-encoded libraries

DOS:

Diversity-oriented synthesis

ELISA:

Enzyme-linked immunosorbent assay

MAPK:

Mitogen-activated protein kinase

PS-SPCL:

Positional-scanning synthetic-peptide combinatorial library

TOS:

Targeted-oriented synthesis

VEGFR2:

Vascular endothelial growth factor receptor 2

References

  • Angata T, Varki A (2002) Chemical diversity in the sialic acids and related alpha-keto acids: an evolutionary perspective. Chem Rev 102:439–469

    Article  CAS  PubMed  Google Scholar 

  • Aretz J et al (2014) Computational and experimental prediction of human C-type lectin receptor druggability. Front Immunol 5:323

    Article  PubMed  PubMed Central  Google Scholar 

  • Barnes C, Balasubramanian S (2000) Recent developments in the encoding and deconvolution of combinatorial libraries. Curr Opin Chem Biol 4:346–350

    Article  CAS  PubMed  Google Scholar 

  • Bleicher KH et al (2003) Hit and lead generation: beyond high-throughput screening. Nat Rev Drug Discov 2:369–378

    Article  CAS  PubMed  Google Scholar 

  • Bunin BA, Ellman JA (1992) A general and expedient method for the solid-phase synthesis of 1,4-benzodiazepine derivatives. J Am Chem Soc 114:10997–10998

    Article  CAS  Google Scholar 

  • Burke MD, Schreiber SL (2004) A planning strategy for diversity-oriented synthesis. Angew Chem Int Ed Engl 43:46–58

    Article  PubMed  Google Scholar 

  • Carney S (2005) How can we avoid the productivity gap? Drug Discov Today 10:1011–1013

    Article  PubMed  Google Scholar 

  • Clark MA et al (2009) Design, synthesis and selection of DNA-encoded small-molecule libraries. Nat Chem Biol 5:647–654

    Article  CAS  PubMed  Google Scholar 

  • Crowley JI, Rapoport H (1976) Solid-phase organic synthesis: novelty or fundamental concept? Acc Chem Res 9:135–144

    Article  CAS  Google Scholar 

  • De Leon-Rodriguez LM et al (2010) MRI detection of VEGFR2 in vivo using a low molecular weight peptoid-(Gd)8-dendron for targeting. J Am Chem Soc 132:12829–12831

    Article  PubMed  PubMed Central  Google Scholar 

  • Ernst B, Magnani JL (2009) From carbohydrate leads to glycomimetic drugs. Nat Rev Drug Discov 8:661–677

    Article  CAS  PubMed  Google Scholar 

  • Gagneux P, Varki A (1999) Evolutionary considerations in relating oligosaccharide diversity to biological function. Glycobiology 9:747–755

    Article  CAS  PubMed  Google Scholar 

  • Galloway WR, Isidro-Llobet A, Spring DR (2010) Diversity-oriented synthesis as a tool for the discovery of novel biologically active small molecules. Nat Commun 1:80

    Article  PubMed  Google Scholar 

  • Geijtenbeek TB et al (2000) DC-SIGN, a dendritic cell-specific HIV-1-binding protein that enhances trans-infection of T cells. Cell 100:587–597

    Article  CAS  PubMed  Google Scholar 

  • Geysen HM, Meloen RH, Barteling SJ (1984) Use of peptide synthesis to probe viral antigens for epitopes to a resolution of a single amino acid. Proc Natl Acad Sci U S A 81:3998–4002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hemmer B et al (1998) The use of soluble synthetic peptide combinatorial libraries to determine antigen recognition of T cells. J Pept Res 52:338–345

    Article  CAS  PubMed  Google Scholar 

  • Hodgson J (2001) ADMET–turning chemicals into drugs. Nat Biotechnol 19:722–726

    Article  CAS  PubMed  Google Scholar 

  • Hopkins AL, Groom CR (2002) The druggable genome. Nat Rev Drug Discov 1:727–730

    Article  CAS  PubMed  Google Scholar 

  • Houghten RA (1985) General method for the rapid solid-phase synthesis of large numbers of peptides: specificity of antigen-antibody interaction at the level of individual amino acids. Proc Natl Acad Sci U S A 82:5131–5135

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Houghten RA (2000) Parallel array and mixture-based synthetic combinatorial chemistry: tools for the next millennium. Annu Rev Pharmacol Toxicol 40:273–282

    Article  CAS  PubMed  Google Scholar 

  • Houghten RA et al (1991) Generation and use of synthetic peptide combinatorial libraries for basic research and drug discovery. Nature 354:84–86

    Article  CAS  PubMed  Google Scholar 

  • Kim CU et al (1997) Influenza neuraminidase inhibitors possessing a novel hydrophobic interaction in the enzyme active site: design, synthesis, and structural analysis of carbocyclic sialic acid analogues with potent anti-influenza activity. J Am Chem Soc 119:681–690

    Article  CAS  PubMed  Google Scholar 

  • Kodadek T (2010) Rethinking screening. Nat Chem Biol 6:162–165

    Article  CAS  PubMed  Google Scholar 

  • Koonin EV, Wolf YI, Karev GP (2002) The structure of the protein universe and genome evolution. Nature 420:218–223

    Article  CAS  PubMed  Google Scholar 

  • Kopp F et al (2012) A diversity-oriented synthesis approach to macrocycles via oxidative ring expansion. Nat Chem Biol 8:358–365

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Laine RA (1994) Invited commentary: a calculation of all possible oligosaccharide isomers both branched and linear yields 1.05 × 1012 structures for a reducing hexasaccharide: the Isomer Barrier to development of single-method saccharide sequencing or synthesis systems. Glycobiology 4:759–767

    Article  CAS  PubMed  Google Scholar 

  • Lasky LA (1992) Selectins: interpreters of cell-specific carbohydrate information during inflammation. Science 258:964–969

    Article  CAS  PubMed  Google Scholar 

  • Leibeling M et al (2010) Domino access to highly substituted chromans and isochromans from carbohydrates. Nat Chem Biol 6:199–201

    Article  CAS  PubMed  Google Scholar 

  • Lepenies B, Yin J, Seeberger PH (2010) Applications of synthetic carbohydrates to chemical biology. Curr Opin Chem Biol 14:404–411

    Article  CAS  PubMed  Google Scholar 

  • Leznoff CC, Wong JY (1973) The use of polymer supports in organic synthesis. III. Selective chemical reactions on one aldehyde group of symmetrical dialdehydes. Can J Chem 51:3756–3764

    Article  CAS  Google Scholar 

  • Liu FT, Rabinovich GA (2005) Galectins as modulators of tumour progression. Nat Rev Cancer 5:29–41

    Article  CAS  PubMed  Google Scholar 

  • McGovern SL et al (2002) A common mechanism underlying promiscuous inhibitors from virtual and high-throughput screening. J Med Chem 45:1712–1722

    Article  CAS  PubMed  Google Scholar 

  • Merrifield RB (1963) Solid phase peptide synthesis. I. The synthesis of a tetrapeptide. J Am Chem Soc 85:2149–2154

    Article  CAS  Google Scholar 

  • Nadin A, Hattotuwagama C, Churcher I (2012) Lead-oriented synthesis: a new opportunity for synthetic chemistry. Angew Chem Int Ed Engl 51:1114–1122

    Article  CAS  PubMed  Google Scholar 

  • Nefzi A et al (2004) Combinatorial chemistry: libraries from libraries, the art of the diversity-oriented transformation of resin-bound peptides and chiral polyamides to low molecular weight acyclic and heterocyclic compounds. J Org Chem 69:3603–3609

    Article  CAS  PubMed  Google Scholar 

  • Nilsson EC et al (2011) The GD1a glycan is a cellular receptor for adenoviruses causing epidemic keratoconjunctivitis. Nat Med 17:105–109

    Article  CAS  PubMed  Google Scholar 

  • O’Reilly MK, Paulson JC (2009) Siglecs as targets for therapy in immune-cell-mediated disease. Trends Pharmacol Sci 30:240–248

    Article  PubMed  PubMed Central  Google Scholar 

  • Ostresh JM et al (1994) “Libraries from libraries”: chemical transformation of combinatorial libraries to extend the range and repertoire of chemical diversity. Proc Natl Acad Sci U S A 91:11138–11142

    Article  PubMed  PubMed Central  Google Scholar 

  • Patterson DE et al (1996) Neighborhood behavior: a useful concept for validation of “molecular diversity” descriptors. J Med Chem 39:3049–3059

    Article  CAS  PubMed  Google Scholar 

  • Pieters RJ (2007) Intervention with bacterial adhesion by multivalent carbohydrates. Med Res Rev 27:796–816

    Article  CAS  PubMed  Google Scholar 

  • Pinilla C et al (1992) Rapid identification of high affinity peptide ligands using positional scanning synthetic peptide combinatorial libraries. Biotechniques 13:901–905

    CAS  PubMed  Google Scholar 

  • Pinilla C, Appel JR, Houghten RA (1994) Investigation of antigen-antibody interactions using a soluble, non-support-bound synthetic decapeptide library composed of four trillion (4 × 10(12) sequences. Biochem J 301(Pt 3):847–853

    Google Scholar 

  • Pinilla C et al (2003) Advances in the use of synthetic combinatorial chemistry: mixture-based libraries. Nat Med 9:118–122

    Article  CAS  PubMed  Google Scholar 

  • Plante OJ, Andrade RB, Seeberger PH (1999) Synthesis and use of glycosyl phosphates as glycosyl donors. Org Lett 1:211–214

    Article  CAS  PubMed  Google Scholar 

  • Plante OJ, Palmacci ER, Seeberger PH (2001) Automated solid-phase synthesis of oligosaccharides. Science 291:1523–1527

    Article  CAS  PubMed  Google Scholar 

  • Redfern OC, Dessailly B, Orengo CA (2008) Exploring the structure and function paradigm. Curr Opin Struct Biol 18:394–402

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Routenberg Love K, Seeberger PH (2004) Automated solid-phase synthesis of protected tumor-associated antigen and blood group determinant oligosaccharides. Angew Chem Int Ed Engl 43:602–605

    Article  PubMed  Google Scholar 

  • Sauer WH, Schwarz MK (2003) Molecular shape diversity of combinatorial libraries: a prerequisite for broad bioactivity. J Chem Inf Comput Sci 43:987–1003

    Article  CAS  PubMed  Google Scholar 

  • Schreiber SL (2000) Target-oriented and diversity-oriented organic synthesis in drug discovery. Science 287:1964–1969

    Article  CAS  PubMed  Google Scholar 

  • Schreiber SL (2009) Organic chemistry: molecular diversity by design. Nature 457:153–154

    Article  CAS  PubMed  Google Scholar 

  • Seeberger PH (2008) Automated oligosaccharide synthesis. Chem Soc Rev 37:19–28

    Article  CAS  PubMed  Google Scholar 

  • Seeberger PH, Rademacher C (eds) (2014) Carbohydrates as drugs. Springer, Heidelberg

    Google Scholar 

  • Seeberger PH, Werz DB (2005) Automated synthesis of oligosaccharides as a basis for drug discovery. Nat Rev Drug Discov 4:751–763

    Article  CAS  PubMed  Google Scholar 

  • Shelke SV et al (2010) A fragment-based in situ combinatorial approach to identify high-affinity ligands for unknown binding sites. Angew Chem Int Ed Engl 49:5721–5725

    Article  CAS  PubMed  Google Scholar 

  • Simon RJ et al (1992) Peptoids: a modular approach to drug discovery. Proc Natl Acad Sci U S A 89:9367–9371

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Smith GP (1985) Filamentous fusion phage: novel expression vectors that display cloned antigens on the virion surface. Science 228:1315–1317

    Article  CAS  PubMed  Google Scholar 

  • Sorme P et al (2005) Structural and thermodynamic studies on cation-Pi interactions in lectin-ligand complexes: high-affinity galectin-3 inhibitors through fine-tuning of an arginine-arene interaction. J Am Chem Soc 127:1737–1743

    Article  PubMed  Google Scholar 

  • Stumpfe D, Bajorath J (2011) Similarity searching. WIREs Comput Mol Sci 1:260–282

    Article  CAS  Google Scholar 

  • Tan DS (2005) Diversity-oriented synthesis: exploring the intersections between chemistry and biology. Nat Chem Biol 1:74–84

    Article  CAS  PubMed  Google Scholar 

  • Tannert R et al (2010) Synthesis and structure-activity correlation of natural-product inspired cyclodepsipeptides stabilizing F-actin. J Am Chem Soc 132:3063–3077

    Article  CAS  PubMed  Google Scholar 

  • Udugamasooriya DG et al (2008) A peptoid “antibody surrogate” that antagonizes VEGF receptor 2 activity. J Am Chem Soc 130:5744–5752

    Article  CAS  PubMed  Google Scholar 

  • Varki A (2006) Nothing in glycobiology makes sense, except in the light of evolution. Cell 126:841–845

    Article  CAS  PubMed  Google Scholar 

  • von Itzstein M et al (1993) Rational design of potent sialidase-based inhibitors of influenza virus replication. Nature 363:418–423

    Article  Google Scholar 

  • Walters WP et al (2011) What do medicinal chemists actually make? A 50-year retrospective. J Med Chem 54:6405–6416

    Article  CAS  PubMed  Google Scholar 

  • Weiner AJ et al (1992) Evidence for immune selection of hepatitis C virus (HCV) putative envelope glycoprotein variants: potential role in chronic HCV infections. Proc Natl Acad Sci U S A 89:3468–3472

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wetzel S et al (2011) Biology-oriented synthesis. Angew Chem Int Ed Engl 50:10800–10826

    Article  CAS  PubMed  Google Scholar 

  • Wong JY, Leznoff CC (1973) The use of polymer supports in organic synthesis. II. The syntheses of monoethers of symmetrical diols. Can J Chem 51:2452–2456

    Article  CAS  Google Scholar 

  • Worth CL, Gong S, Blundell TL (2009) Structural and functional constraints in the evolution of protein families. Nat Rev Mol Cell Biol 10:709–720

    CAS  PubMed  Google Scholar 

  • Young DW (2010) Synthetic chemistry: an upfront investment. Nat Chem Biol 6:174–175

    Article  CAS  PubMed  Google Scholar 

  • Zhao H (2007) Scaffold selection and scaffold hopping in lead generation: a medicinal chemistry perspective. Drug Discov Today 12:149–155

    Article  CAS  PubMed  Google Scholar 

  • Zuckermann RN, Kodadek T (2009) Peptoids as potential therapeutics. Curr Opin Mol Ther 11:299–307

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Biomolecular Systems, Max Planck Institute of Colloids and Interfaces, Am Mühlenberg 1, 14476, Potsdam, Germany

    C. Rademacher & P. H. Seeberger

  2. Institute of Chemistry and Biochemistry, Freie Universität Berlin, Arnimallee 22, 14195, Berlin, Germany

    C. Rademacher & P. H. Seeberger

Authors
  1. C. Rademacher
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. P. H. Seeberger
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to C. Rademacher .

Editor information

Editors and Affiliations

  1. Drug Discovery-Cross Indication Platform, Bayer Pharma AG, Wuppertal, Germany

    Ulrich Nielsch

  2. Drug Discovery-Cross Indication Platform, Bayer Pharma AG, Berlin, Berlin, Germany

    Ulrike Fuhrmann

  3. Drug Discovery-Global External Innovation & Alliances, Bayer Pharma AG, Berlin, Berlin, Germany

    Stefan Jaroch

Rights and permissions

Reprints and permissions

Copyright information

© 2015 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Rademacher, C., Seeberger, P.H. (2015). High-Throughput Synthesis of Diverse Compound Collections for Lead Discovery and Optimization. In: Nielsch, U., Fuhrmann, U., Jaroch, S. (eds) New Approaches to Drug Discovery. Handbook of Experimental Pharmacology, vol 232. Springer, Cham. https://doi.org/10.1007/164_2015_25

Download citation

Publish with us

Policies and ethics

Search

Navigation