One of the initial steps in the development of therapeutic agents is the identification of lead compounds that bind to the receptor or enzyme target of interest. Many analogs of these lead compounds are then synthesized to define the key recognition elements for maximal activity. In general, many compounds must be evaluated in both the lead identification and optimization steps. Increasing burdens have been placed on these efforts due to the large number of new therapeutic targets that continue to be identified thorough modern molecular biology methods.1 To address this demand, very powerful chemical and biological methods have been developed for the generation of large combinatorial libraries of peptides2 and oligonucleotides3 that are then screened against a receptor or enzyme to identify high-affinity ligands or potent inhibitors, respectively. While these studies have clearly demonstrated the power of library synthesis and screening strategies, peptides and oligonucleotides generally have poor oral activities and rapid in vivo clearance;4 therefore their utility as bioavailable therapeutic agents is often limited. Due to the favorable pharmacokinetic properties of many small organic molecules (<600-700 molecular weight),5 the design, synthesis, and evaluation of libraries of these compounds6 has rapidly become a major frontier in organic chemistry. Lorin A. Thompson was born in Lexington, KY, in 1970. He received the Bachelor of Science degree from the University of North Carolina, Chapel Hill, in 1992 where he worked under the guidance of Joseph Desimone. He is currently pursuing his doctorate in the laboratory of Jonathan Ellman at UC Berkeley where he is the 1994 Glaxo-Wellcome fellow. His research interests include the development of synthetic methodology for organic library construction.

/pdf/synthesis-and-applications-of-small-molecule-libraries-3n3gol8dyk.pdf

Synthesis and Applications of Small Molecule Libraries.

1. Peptoids 419 2. Oligocarbamates 420 3. Oligoureas 420 4. Vinylogous Sulfonyl Peptides 420 5. Peptidosulfonamides 420 6. Azatides 420 7. Ketides 420 D. Small Molecule Libraries 420 1. Acyclic Libraries 422 2. Libraries on Preformed Scaffolds 422 3. Heterocyclic Libraries 423 4. Structurally Heterogeneous Libraries 427 E. Cleavable Linkers 428 1. Single Cleavable Linkers 428 2. Multiply Cleavable Linkers 429 IV. Screening Methods 432 A. On-Bead Screening 432 1. Binding Assay 432 2. Functional Assay 434 B. Solution-Phase Screening 434 1. The 96-Well Two-Stage Releasable Assays 435

/pdf/the-one-bead-one-compound-combinatorial-library-method-10r4u9b736.pdf

The “One-Bead-One-Compound” Combinatorial Library Method

Combinatorial synthesis : the design of compound libraries and their application to drug discovery

The Current Status of Heterocyclic Combinatorial Libraries.

Neuropeptides--an overview

A synthetic combinatorial library containing 52,128,400 D-amino acid hexapeptides was used to identify a ligand for the mu opioid receptor. The peptide, Ac-rfwink-NH2, bears no resemblance to any known opioid peptide. Simulations using molecular dynamics, however, showed that three amino acid moieties have the same spatial orientation as the corresponding pharmacophoric groups of the opioid peptide PLO17. Ac-rfwink-NH2 was shown to be a potent agonist at the mu receptor and induced long-lasting analgesia in mice. Analgesia produced by intraperitoneally administered Ac-rfwink-NH2 was blocked by intracerebroventricular administration of naloxone, demonstrating that this peptide may cross the blood-brain barrier.

https://science.sciencemag.org/content/sci/266/5193/2019.full.pdf

An all D-amino acid opioid peptide with central analgesic activity from a combinatorial library

A synthetic peptide combinatorial library made up of 52,128,400 hexapeptides, each having an acetyl group at the N terminus and an amide group on the C terminus, was screened to find compounds able to displace tritiated [D-Ala2,MePhe4,Gly-ol5]enkephalin from mu opioid receptor binding sites in crude rat brain homogenates. Individual peptides with mu receptor affinity were found using an iterative process for successively determining the most active peptide mixtures. Upon completion of this iterative process, the three peptides with the highest affinity were Ac-RFMWMT-NH2, Ac-RFMWMR-NH2, and Ac-RFMWMK-NH2. These peptides showed high affinity for mu and kappa 3 opioid receptors, somewhat lower affinity for delta receptors, weak affinity for kappa 1 receptors, and no affinity for kappa 2 receptors. They were found to be potent mu receptor antagonists in the guinea pig ileum assay and relatively weak antagonists in the mouse vas deferens assay. These peptides represent a class of opioid receptor ligands that we have termed acetalins (acetyl plus enkephalin).

Acetalins: opioid receptor antagonists determined through the use of synthetic peptide combinatorial libraries

Two synthetic combinatorial libraries (SCLs) were prepared, each composed of 52,128,400 L-amino acid hexapeptides, one with and the other without an N-terminal acetyl moiety. The two libraries were used in conjunction with an iterative selection process to identify individual peptides capable of inhibiting the binding of the mu-selective opioid peptide [3H]-[D-Ala2,MePhe4,Gly-ol5]enkephalin to rat brain homogenates. As reported previously, when using the nonacetylated SCL the first five residues identified corresponded exactly to methionine- and leucine-enkephalin, both of which are endogenous opioid peptides. The iterative identification process has now been completed for two additional mixtures found to have activity in the initial screening of this SCL. Two new series unrelated to the enkephalins have been identified: YPFGFO-NH2 and WWPKHO-NH2 (where O = one of the 20 L-amino acids). Individual peptides from each of these were found to be agonists at the mu receptor and have high affinity (IC50 values of the most active peptides were 10-15 nM) and selectivity for the mu receptor. In addition to the acetalins (described previously), two new series have now been identified from the acetylated library: Ac-FRWWYO-NH2 and Ac-RWIG-WO-NH2 (IC50 values of the most active peptides were 5-30 nM). Ac-FRWWYM-NH2 was determined to be an agonist at the mu receptor, whereas Ac-RWIGWR-NH2 was found to be an antagonist at this receptor.

N N Chung

Papers

An all D-amino acid opioid peptide with central analgesic activity from a combinatorial library

Acetalins: opioid receptor antagonists determined through the use of synthetic peptide combinatorial libraries

Six highly active mu-selective opioid peptides identified from two synthetic combinatorial libraries.