Small molecule
Encyclopedia
In the fields of pharmacology
and biochemistry
, a small molecule is a low molecular weight organic compound
which is by definition not a polymer
. The term small molecule, especially within the field of pharmacology, is usually restricted to a molecule that also binds with high affinity to a biopolymer
such as protein
, nucleic acid
, or polysaccharide
and in addition alters the activity or function of the biopolymer. The upper molecular weight limit for a small molecule is approximately 800 Daltons
which allows for the possibility to rapidly diffuse across cell membranes so that they can reach intracellular
sites of action. In addition, this molecular weight cutoff is a necessary but insufficient condition for oral bioavailability
.
Small molecules can have a variety of biological functions, serving as cell signaling
molecules, as tools in molecular biology
, as drug
s in medicine
, as pesticide
s in farming, and in many other roles. These compounds can be natural (such as secondary metabolites) or artificial (such as antiviral drug
s); they may have a beneficial effect against a disease (such as drugs) or may be detrimental (such as teratogens and carcinogen
s).
Biopolymers such as nucleic acid
s, protein
s, and polysaccharides (such as starch
or cellulose
) are not small molecules, although their constituent monomers — ribo- or deoxyribonucleotides, amino acid
s, and monosaccharides, respectively — are often considered to be. Very small oligomer
s are also usually considered small molecules, such as dinucleotides, peptides such as the antioxidant glutathione
, and disaccharides such as sucrose
.
. Many proteins are degraded if administered orally and most often cannot cross the cell membrane
s. Small molecules are more likely to be absorbed, although some of them are only absorbed after oral administration if given as prodrug
s. Small molecules are often considered superior to "large molecule" biologics
because they can be taken orally.
Many dietary supplement
s are small molecules (but not herb extracts, such as ginkgo).
), but very common in soil bacteria (such as streptomyces
) and fungi, which in particular secrete antibiotics.
Plants also have several secondary metabolite
s, which play a role in cell signalling, pigmentation or in defence, several of which have also been used as drugs (medical and recreational):
Enzymes and receptors are often activated or inhibited by endogenous protein
, but can be also inhibited by endogenous or exogenous small molecule inhibitors
or activators
with can bind to the active site
or on the allosteric site
.
An example is the teratogen and carcinogen phorbol 12-myristate 13-acetate which is a plant terpene which activates protein kinase C
promoting cancer, making it a very useful investigative tool.
There is also interest in creating small molecule artificial transcription factors to regulate gene expression
, examples include wrenchnol (a wrench shaped molecule).
Binding of ligand
can be characterised using a variety of analytical techniques such as surface plasmon resonance
, microscale thermophoresis
or dual polarisation interferometry
to quantify the reaction affinities and kinetic properties and also any induced conformational change
.
Pharmacology
Pharmacology is the branch of medicine and biology concerned with the study of drug action. More specifically, it is the study of the interactions that occur between a living organism and chemicals that affect normal or abnormal biochemical function...
and biochemistry
Biochemistry
Biochemistry, sometimes called biological chemistry, is the study of chemical processes in living organisms, including, but not limited to, living matter. Biochemistry governs all living organisms and living processes...
, a small molecule is a low molecular weight organic compound
Organic compound
An organic compound is any member of a large class of gaseous, liquid, or solid chemical compounds whose molecules contain carbon. For historical reasons discussed below, a few types of carbon-containing compounds such as carbides, carbonates, simple oxides of carbon, and cyanides, as well as the...
which is by definition not a polymer
Polymer
A polymer is a large molecule composed of repeating structural units. These subunits are typically connected by covalent chemical bonds...
. The term small molecule, especially within the field of pharmacology, is usually restricted to a molecule that also binds with high affinity to a biopolymer
Biopolymer
Biopolymers are polymers produced by living organisms. Since they are polymers, Biopolymers contain monomeric units that are covalently bonded to form larger structures. There are three main classes of biopolymers based on the differing monomeric units used and the structure of the biopolymer formed...
such as protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
, nucleic acid
Nucleic acid
Nucleic acids are biological molecules essential for life, and include DNA and RNA . Together with proteins, nucleic acids make up the most important macromolecules; each is found in abundance in all living things, where they function in encoding, transmitting and expressing genetic information...
, or polysaccharide
Polysaccharide
Polysaccharides are long carbohydrate molecules, of repeated monomer units joined together by glycosidic bonds. They range in structure from linear to highly branched. Polysaccharides are often quite heterogeneous, containing slight modifications of the repeating unit. Depending on the structure,...
and in addition alters the activity or function of the biopolymer. The upper molecular weight limit for a small molecule is approximately 800 Daltons
Atomic mass unit
The unified atomic mass unit or dalton is a unit that is used for indicating mass on an atomic or molecular scale. It is defined as one twelfth of the rest mass of an unbound neutral atom of carbon-12 in its nuclear and electronic ground state, and has a value of...
which allows for the possibility to rapidly diffuse across cell membranes so that they can reach intracellular
Intracellular
Not to be confused with intercellular, meaning "between cells".In cell biology, molecular biology and related fields, the word intracellular means "inside the cell".It is used in contrast to extracellular...
sites of action. In addition, this molecular weight cutoff is a necessary but insufficient condition for oral bioavailability
Bioavailability
In pharmacology, bioavailability is a subcategory of absorption and is used to describe the fraction of an administered dose of unchanged drug that reaches the systemic circulation, one of the principal pharmacokinetic properties of drugs. By definition, when a medication is administered...
.
Small molecules can have a variety of biological functions, serving as cell signaling
Cell signaling
Cell signaling is part of a complex system of communication that governs basic cellular activities and coordinates cell actions. The ability of cells to perceive and correctly respond to their microenvironment is the basis of development, tissue repair, and immunity as well as normal tissue...
molecules, as tools in molecular biology
Molecular biology
Molecular biology is the branch of biology that deals with the molecular basis of biological activity. This field overlaps with other areas of biology and chemistry, particularly genetics and biochemistry...
, as drug
Drug
A drug, broadly speaking, is any substance that, when absorbed into the body of a living organism, alters normal bodily function. There is no single, precise definition, as there are different meanings in drug control law, government regulations, medicine, and colloquial usage.In pharmacology, a...
s in medicine
Medicine
Medicine is the science and art of healing. It encompasses a variety of health care practices evolved to maintain and restore health by the prevention and treatment of illness....
, as pesticide
Pesticide
Pesticides are substances or mixture of substances intended for preventing, destroying, repelling or mitigating any pest.A pesticide may be a chemical unicycle, biological agent , antimicrobial, disinfectant or device used against any pest...
s in farming, and in many other roles. These compounds can be natural (such as secondary metabolites) or artificial (such as antiviral drug
Antiviral drug
Antiviral drugs are a class of medication used specifically for treating viral infections. Like antibiotics for bacteria, specific antivirals are used for specific viruses...
s); they may have a beneficial effect against a disease (such as drugs) or may be detrimental (such as teratogens and carcinogen
Carcinogen
A carcinogen is any substance, radionuclide, or radiation that is an agent directly involved in causing cancer. This may be due to the ability to damage the genome or to the disruption of cellular metabolic processes...
s).
Biopolymers such as nucleic acid
Nucleic acid
Nucleic acids are biological molecules essential for life, and include DNA and RNA . Together with proteins, nucleic acids make up the most important macromolecules; each is found in abundance in all living things, where they function in encoding, transmitting and expressing genetic information...
s, protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
s, and polysaccharides (such as starch
Starch
Starch or amylum is a carbohydrate consisting of a large number of glucose units joined together by glycosidic bonds. This polysaccharide is produced by all green plants as an energy store...
or cellulose
Cellulose
Cellulose is an organic compound with the formula , a polysaccharide consisting of a linear chain of several hundred to over ten thousand β linked D-glucose units....
) are not small molecules, although their constituent monomers — ribo- or deoxyribonucleotides, amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
s, and monosaccharides, respectively — are often considered to be. Very small oligomer
Oligomer
In chemistry, an oligomer is a molecule that consists of a few monomer units , in contrast to a polymer that, at least in principle, consists of an unlimited number of monomers. Dimers, trimers, and tetramers are oligomers. Many oils are oligomeric, such as liquid paraffin...
s are also usually considered small molecules, such as dinucleotides, peptides such as the antioxidant glutathione
Glutathione
Glutathione is a tripeptide that contains an unusual peptide linkage between the amine group of cysteine and the carboxyl group of the glutamate side-chain...
, and disaccharides such as sucrose
Sucrose
Sucrose is the organic compound commonly known as table sugar and sometimes called saccharose. A white, odorless, crystalline powder with a sweet taste, it is best known for its role in human nutrition. The molecule is a disaccharide composed of glucose and fructose with the molecular formula...
.
Drugs
Most drugs are small molecules, although some drugs can be proteins, e.g. insulinInsulin
Insulin is a hormone central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle....
. Many proteins are degraded if administered orally and most often cannot cross the cell membrane
Cell membrane
The cell membrane or plasma membrane is a biological membrane that separates the interior of all cells from the outside environment. The cell membrane is selectively permeable to ions and organic molecules and controls the movement of substances in and out of cells. It basically protects the cell...
s. Small molecules are more likely to be absorbed, although some of them are only absorbed after oral administration if given as prodrug
Prodrug
A prodrug is a pharmacological substance administered in an inactive form. Once administered, the prodrug is metabolised in vivo into an active metabolite, a process termed bioactivation. The rationale behind the use of a prodrug is generally for absorption, distribution, metabolism, and...
s. Small molecules are often considered superior to "large molecule" biologics
Biologics
A biologic is a medicinal product such as a vaccine, blood or blood component, allergenic, somatic cell, gene therapy, tissue, recombinant therapeutic protein, or living cells that are used as therapeutics to treat diseases...
because they can be taken orally.
Many dietary supplement
Dietary supplement
A dietary supplement, also known as food supplement or nutritional supplement, is a preparation intended to supplement the diet and provide nutrients, such as vitamins, minerals, fiber, fatty acids, or amino acids, that may be missing or may not be consumed in sufficient quantities in a person's diet...
s are small molecules (but not herb extracts, such as ginkgo).
Primary and secondary metabolites
For organisms to produce small molecules they need one or more specialized enzymes (to create and destroy), which as a result are not that varied in vertebrates (recent and small + slow population sizeNearly neutral theory of molecular evolution
The nearly neutral theory of molecular evolution is a modification of the neutral theory of molecular evolution that accounts for slightly advantageous or deleterious mutations at the molecular level...
), but very common in soil bacteria (such as streptomyces
Streptomyces
Streptomyces is the largest genus of Actinobacteria and the type genus of the family Streptomycetaceae. Over 500 species of Streptomyces bacteria have been described. As with the other Actinobacteria, streptomycetes are gram-positive, and have genomes with high guanine and cytosine content...
) and fungi, which in particular secrete antibiotics.
Plants also have several secondary metabolite
Secondary metabolite
Secondary metabolites are organic compounds that are not directly involved in the normal growth, development, or reproduction of an organism. Unlike primary metabolites, absence of secondary metabolities does not result in immediate death, but rather in long-term impairment of the organism's...
s, which play a role in cell signalling, pigmentation or in defence, several of which have also been used as drugs (medical and recreational):
- Alkaloids
- Glycosides
- Lipids
- Flavonoids
- Nonribosomal peptideNonribosomal peptideNonribosomal peptides are a class of peptide secondary metabolites, usually produced by microorganisms like bacteria and fungi. Nonribosomal peptides are also found in higher organisms, such as nudibranchs, but are thought to be made by bacteria inside these organisms...
s, such as actinomycin-D - Phenazines
- PhenolsPhenolsIn organic chemistry, phenols, sometimes called phenolics, are a class of chemical compounds consisting of a hydroxyl group bonded directly to an aromatic hydrocarbon group...
- PolyketidePolyketidePolyketides are secondary metabolites from bacteria, fungi, plants, and animals. Polyketides are usually biosynthesized through the decarboxylative condensation of malonyl-CoA derived extender units in a similar process to fatty acid synthesis...
- Terpenes, including steroids
- Tetrapyrroles.
Research tools
Ligand (biochemistry)
In biochemistry and pharmacology, a ligand is a substance that forms a complex with a biomolecule to serve a biological purpose. In a narrower sense, it is a signal triggering molecule, binding to a site on a target protein.The binding occurs by intermolecular forces, such as ionic bonds, hydrogen...
, but can be also inhibited by endogenous or exogenous small molecule inhibitors
Enzyme inhibitor
An enzyme inhibitor is a molecule that binds to enzymes and decreases their activity. Since blocking an enzyme's activity can kill a pathogen or correct a metabolic imbalance, many drugs are enzyme inhibitors. They are also used as herbicides and pesticides...
or activators
Enzyme inhibitor
An enzyme inhibitor is a molecule that binds to enzymes and decreases their activity. Since blocking an enzyme's activity can kill a pathogen or correct a metabolic imbalance, many drugs are enzyme inhibitors. They are also used as herbicides and pesticides...
with can bind to the active site
Active site
In biology the active site is part of an enzyme where substrates bind and undergo a chemical reaction. The majority of enzymes are proteins but RNA enzymes called ribozymes also exist. The active site of an enzyme is usually found in a cleft or pocket that is lined by amino acid residues that...
or on the allosteric site
Allosteric regulation
In biochemistry, allosteric regulation is the regulation of an enzyme or other protein by binding an effector molecule at the protein's allosteric site . Effectors that enhance the protein's activity are referred to as allosteric activators, whereas those that decrease the protein's activity are...
.
An example is the teratogen and carcinogen phorbol 12-myristate 13-acetate which is a plant terpene which activates protein kinase C
Protein kinase C
Protein kinase C also known as PKC is a family of enzymes that are involved in controlling the function of other proteins through the phosphorylation of hydroxyl groups of serine and threonine amino acid residues on these proteins. PKC enzymes in turn are activated by signals such as increases in...
promoting cancer, making it a very useful investigative tool.
There is also interest in creating small molecule artificial transcription factors to regulate gene expression
Gene expression
Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product. These products are often proteins, but in non-protein coding genes such as ribosomal RNA , transfer RNA or small nuclear RNA genes, the product is a functional RNA...
, examples include wrenchnol (a wrench shaped molecule).
Binding of ligand
Ligand (biochemistry)
In biochemistry and pharmacology, a ligand is a substance that forms a complex with a biomolecule to serve a biological purpose. In a narrower sense, it is a signal triggering molecule, binding to a site on a target protein.The binding occurs by intermolecular forces, such as ionic bonds, hydrogen...
can be characterised using a variety of analytical techniques such as surface plasmon resonance
Surface plasmon resonance
The excitation of surface plasmons by light is denoted as a surface plasmon resonance for planar surfaces or localized surface plasmon resonance for nanometer-sized metallic structures....
, microscale thermophoresis
Microscale Thermophoresis
Microscale Thermophoresis is a technology for the analysis of biomolecules. Microscale Thermophoresis is the directed movement of particles in a microscopic temperature gradient...
or dual polarisation interferometry
Dual Polarisation Interferometry
Dual polarization interferometry is an analytical technique that can probe molecular scale layers adsorbed to the surface of a waveguide by using the evanescent wave of a laser beam confined to the waveguide...
to quantify the reaction affinities and kinetic properties and also any induced conformational change
Conformational change
A macromolecule is usually flexible and dynamic. It can change its shape in response to changes in its environment or other factors; each possible shape is called a conformation, and a transition between them is called a conformational change...
.