A lead compound (, i.e. a "leading" compound, not to be confused with various compounds of the
metal
A metal (from Greek μέταλλον ''métallon'', "mine, quarry, metal") is a material that, when freshly prepared, polished, or fractured, shows a lustrous appearance, and conducts electricity and heat relatively well. Metals are typi ...
lic element
lead
Lead is a chemical element with the Symbol (chemistry), symbol Pb (from the Latin ) and atomic number 82. It is a heavy metals, heavy metal that is density, denser than most common materials. Lead is Mohs scale of mineral hardness#Intermediate ...
) 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 by ...
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 ele ...
that has
pharmacological
Pharmacology is a branch of medicine, biology and pharmaceutical sciences concerned with drug or medication action, where a drug may be defined as any artificial, natural, or endogenous (from within the body) molecule which exerts a biochemic ...
or
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 determination includes a chemist's specifying the molecular geometry and, when feasible and necessary, the electronic structure of the target molecule or other solid. Molecular geometry refers to the spatial arrangement of a ...
serves as a starting point for
chemical
A chemical substance is a form of matter having constant chemical composition and characteristic properties. Some references add that chemical substance cannot be separated into its constituent elements by physical separation methods, i.e., wit ...
modifications in order to improve
potency,
selectivity, or
pharmacokinetic
Pharmacokinetics (from Ancient Greek ''pharmakon'' "drug" and ''kinetikos'' "moving, putting in motion"; see chemical kinetics), sometimes abbreviated as PK, is a branch of pharmacology dedicated to determining the fate of substances administered ...
parameters. Furthermore, newly invented pharmacologically active
moieties may have poor
druglikeness 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 experimentation especially used in drug discovery and relevant to the fields of biology, materials science and chemistry. Using robotics, data processing/control software, liquid handlin ...
s (active compounds are designated as "hits") which can screen compounds for their ability to inhibit (
antagonist) or stimulate (
agonist
An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ago ...
) 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
A natural product is a natural compound or substance produced by a living organism—that is, found in nature. In the broadest sense, natural products include any substance produced by life. Natural products can also be prepared by chemical sy ...
, employing
combinatorial chemistry Combinatorial chemistry comprises chemical synthetic methods that make it possible to prepare a large number (tens to thousands or even millions) of compounds in a single process. These compound libraries can be made as mixtures, sets of individua ...
, or by
molecular modeling as in
rational drug design.
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.
See also
*
Drug development
Drug development is the process of bringing a new pharmaceutical drug to the market once a lead compound has been identified through the process of drug discovery. It includes preclinical research on microorganisms and animals, filing for r ...
*
Drug design
Drug design, often referred to as rational drug design or simply rational design, is the inventive process of finding new medications based on the knowledge of a biological target. The drug is most commonly an organic small molecule that ac ...
*
Rational drug design
*
Drug discovery hit to lead
*
Lead optimization
References
{{reflist
Drug discovery
Medicinal chemistry