Lead Discovery (Target to Lead)

In Lead Discovery, the processes that identify small molecule leads are considerably different from those that identify biomolecular leads.

Lead Discovery for Small Molecules or Peptides

For small molecules or peptides, the project team strives to: Develop an in vitro assay with a tool agent that will identify other agents which interact with the target through the desired mechanism of action; Create variants of the target and assay amenable for screening preferentially in high throughput mode; and Identify first agents (leads) through screening.

Screening strategies for identifying small molecule or peptide hits include

  • Focused (Selected Compound Set) Screening
  • High Throughput (Diversity) Screening
  • Structure Based Design
  • Fragment Based (Reduced Complexity) Screening

Once potential hits have been identified medicinal chemists get involved in determining which families of hits are sufficiently druggable to justify chemical exploration of the series to identify lead series for lead optimization.

A discussion of the science of small molecule lead identification is beyond the scope of this website.  The reader may enjoy the following references (e.g. the relevant chapters in the following books). 1, 2   The tracking of progress in this phase may be found in the section Project Tracking in Drug Discovery.

Lead Discovery for Protein-Based Drugs

The processes that identify protein leads are considerably different and vary according to the type of macromolecule.  In general, this stage is considerably shorter for protein-based drugs. It is beyond the scope of this discussion to delve into the process of protein-based drug discovery.  The reader may wish to refer to the following references. 3, 4, 5

The mode of action of a protein-based drug can differ considerably from the mode of action of a small molecule drug.  A small molecule invariably is designed to interact with a biological target, as is the case with protein-based drugs.  But the pharmacology of protein-based drugs is considerably more diverse.  In the classical lock-and-key model, the protein-based drug could be the key, as in hormone replacement therapy.  The protein-based drug could bind to the key (ligand binding) or it could be an extracellular portion of the receptor, as in decoy therapy.   A protein-based drug can even have enzymatic activity, e.g tissue plasminogen activator (t-PA).  Your portfolio nomenclature system needs to account for these diverse possibilities.

Small molecules often mimic a protein that is the natural ligand for the target of interest, at least in the manner of binding to the target.  There are a number of marketed drugs that are natural ligands for targets.6

  1. Bert Spilker, “Guide to Drug Development, A Comprehensive Review and Assessment”, Wolters Kluwer, Lippincott Williams & Wilkins, New York, 2009, p. 119-131
  2. Rick Ng, “Drugs, from Discovery to Approval”, 2nd Ed. 2009.
  3. Recent advances in protein-based drug discovery are discussed in D.S. Gill, and N.K. Damle, “Biopharmaceutical drug discovery using novel protein scaffolds”, Current Opinion in Biotechnology 17, 653-658 (2006).
  4. “Biotechnology”, Chapter 12 in Bert Spilker, “Guide to Drug Development, A Comprehensive Review and Assessment”, Wolters Kluwer, Lippincott Williams & Wilkins, New York, 2009, p. 119-131
  5. “Drug Discovery: Large Molecule Drugs”, Chapter 4, Rick Ng, “Drugs, from Discovery to Approval”, 2nd Ed. 2009, pp. 93-135, and other sections relating to biomolecular drugs, e.g. “Manufacture of Large Molecule APIs (Recombinant DNA Methods, Chapter 10.5, pp. 340-348
  6. See “Cytokines” Chapter 4.4, and “Hormones” Chapter 4.5 in “Drugs, from Discovery to Approval”, Rick Ng, Wiley-Blackwell, 2009.


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