A lead compound (, i.e. a "leading" compound, not to be confused with various compounds of the

metal A metal () is a material that, when polished or fractured, shows a lustrous appearance, and conducts electrical resistivity and conductivity, electricity and thermal conductivity, heat relatively well. These properties are all associated wit ...

lic element

lead Lead () is a chemical element; it has Chemical symbol, symbol Pb (from Latin ) and atomic number 82. It is a Heavy metal (elements), heavy metal that is density, denser than most common materials. Lead is Mohs scale, soft and Ductility, malleabl ...

) in

drug discovery In the fields of medicine, biotechnology, and pharmacology, drug discovery is the process by which new candidate medications are discovered. Historically, drugs were discovered by identifying the active ingredient from traditional remedies or ...

is a

chemical compound A chemical compound is a chemical substance composed of many identical molecules (or molecular entities) containing atoms from more than one chemical element held together by chemical bonds. A molecule consisting of atoms of only one element ...

that has

pharmacological Pharmacology is the science of drugs and medications, including a substance's origin, composition, pharmacokinetics, pharmacodynamics, therapeutic use, and toxicology. More specifically, it is the study of the interactions that occur between ...

biological activity In pharmacology, biological activity or pharmacological activity describes the beneficial or adverse effects of a drug on living matter. When a drug is a complex chemical mixture, this activity is exerted by the substance's active ingredient or ...

likely to be therapeutically useful, but may nevertheless have suboptimal structure that requires modification to fit better to the target; lead drugs offer the prospect of being followed by back-up compounds. Its

chemical structure A chemical structure of a molecule is a spatial arrangement of its atoms and their chemical bonds. Its determination includes a chemist's specifying the molecular geometry and, when feasible and necessary, the electronic structure of the target m ...

serves as a starting point for

chemical A chemical substance is a unique form of matter with constant chemical composition and characteristic properties. Chemical substances may take the form of a single element or chemical compounds. If two or more chemical substances can be combin ...

modifications in order to improve potency, selectivity, or pharmacokinetic parameters. Furthermore, newly invented pharmacologically active moieties may have poor

druglikeness Druglikeness is a qualitative concept used in drug design for how "druglike" a substance is with respect to factors like bioavailability. A druglike molecule has properties such as: * Solubility in both water and fat, as an orally administered d ...

and may require chemical modification to become drug-like enough to be tested biologically or clinically.

Terminology

Lead compounds are sometimes called developmental candidates. This is because the discovery and selection of lead compounds occurs prior to preclinical and clinical development of the candidate.

Discovering lead compounds

Discovery of a drugable target

Before lead compounds can be discovered, a suitable target for rational drug design must be selected on the basis of biological plausibility or identified through screening potential lead compounds against multiple targets. Drug libraries are often tested by

high-throughput screening High-throughput screening (HTS) is a method for scientific discovery especially used in drug discovery and relevant to the fields of biology, materials science and chemistry. Using robotics, data processing/control software, liquid handling device ...

s (active compounds are designated as "hits") which can screen compounds for their ability to inhibit (

antagonist An antagonist is a character in a story who is presented as the main enemy or rival of the protagonist and is often depicted as a villain.agonist An agonist is a chemical that activates a Receptor (biochemistry), receptor to produce a biological response. Receptors are Cell (biology), cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an R ...

) a receptor of interest as well as determine their selectivity for them.

Development of a lead compound

A lead compound may arise from a variety of different sources. Lead compounds are found by characterizing natural products, employing combinatorial chemistry, or by molecular modeling as in

rational drug design Drug design, often referred to as rational drug design or simply rational design, is the invention, inventive process of finding new medications based on the knowledge of a biological target. The drug is most commonly an organic compound, organi ...

. Chemicals identified as hits through high-throughput screening may also become lead compounds. Once a lead compound is selected it must undergo lead optimization, which involves making the compound more "drug-like." This is where Lipinski's rule of five comes into play, sometimes also referred to as the "Pfizer rule" or simply as the "rule of five." Other factors, such as the ease of scaling up the manufacturing of the chemical, must be taken into consideration.

References

{{Authority control Drug discovery Medicinal chemistry

Terminology

Discovering lead compounds

Discovery of a drugable target

Development of a lead compound

See also

References