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 typicall ...
lic element
lead
Lead is a chemical element with the symbol Pb (from the Latin ) and atomic number 82. It is a heavy metal that is denser than most common materials. Lead is soft and malleable, and also has a relatively low melting point. When freshly cu ...
) in
drug discovery 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 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 biochemica ...
or
biological activity 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 ...
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., w ...
modifications in order to improve
potency
Potency may refer to:
* Potency (pharmacology), a measure of the activity of a drug in a biological system
* Virility
* Cell potency, a measure of the differentiation potential of stem cells
* In homeopathic dilutions, potency is a measure of how ...
,
selectivity
Selectivity may refer to:
Psychology and behaviour
* Choice, making a selection among options
* Discrimination, the ability to recognize differences
* Socioemotional selectivity theory, in social psychology
Engineering
* Selectivity (radio), a ...
, 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. It is estimated from the molecular structure before the substance is even synthesized and tested. A druglike m ...
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 handling ...
s (active compounds are designated as "hits") which can screen compounds for their ability to inhibit (
antagonist) or stimulate (
agonist) 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
Molecular modelling encompasses all methods, theoretical and computational, used to model or mimic the behaviour of molecules. The methods are used in the fields of computational chemistry, drug design, computational biology and materials scien ...
as in
rational 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 activa ...
.
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
Lipinski's rule of five, also known as Pfizer's rule of five or simply the rule of five (RO5), is a rule of thumb to evaluate druglikeness or determine if a chemical compound with a certain pharmacological or biological activity has chemical pro ...
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 re ...
*
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 acti ...
*
Rational 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 activa ...
*
Drug discovery hit to lead
Hit to lead (H2L) also known as lead generation is a stage in early drug discovery where small molecule hits from a high throughput screen (HTS) are evaluated and undergo limited optimization to identify promising lead compounds. These lead compo ...
*
Lead optimization
Hit to lead (H2L) also known as lead generation is a stage in early drug discovery where small molecule hits from a high throughput screen (HTS) are evaluated and undergo limited optimization to identify promising lead compounds. These lead compo ...
References
{{reflist
Drug discovery
Medicinal chemistry