Small molecule

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Within the fields of molecular biology and pharmacology, a small
molecule or micromolecule is a low molecular weight (≤ 1000 daltons[1]) organic
compound that may regulate a biological process, with a size on the order of 1 nm[citation
needed]
. Many drugs are small molecules; the terms are equivalent in the literature. Larger
structures such as nucleic acids and proteins, and many polysaccharides are not small
molecules, although their constituent monomers (ribo- or deoxyribonucleotides, amino
acids, and monosaccharides, respectively) are often considered small molecules. Small
molecules may be used as research tools to probe biological function as well as leads in
the development of new therapeutic agents. Some can inhibit a specific function of a
protein or disrupt protein–protein interactions.[2]
Pharmacology usually restricts the term "small molecule" to molecules that bind specific
biological macromolecules and act as an effector, altering the activity or function of
the target. Small molecules can have a variety of biological functions or applications,
serving as cell signaling molecules, drugs in medicine, pesticides in farming, and in
many other roles. These compounds can be natural (such as secondary metabolites) or
artificial (such as antiviral drugs); they may have a beneficial effect against a disease
(such as drugs) or may be detrimental (such as teratogens and carcinogens).

Contents

 1Molecular weight cutoff

 2Drugs
 3Secondary metabolites
 4Research tools
 5Anti-genomic therapeutics
 6See also
 7References
 8External links

Molecular weight cutoff[edit]

The upper molecular-weight limit for a small molecule is approximately 900 daltons,
which allows for the possibility to rapidly diffuse across cell membranes so that it can
reach intracellular sites of action.[1][3] This molecular weight cutoff is also a necessary but
insufficient condition for oral bioavailability as it allows for transcellular transport through
intestinal epithelial cells. In addition to intestinal permeability, the molecule must also
possess a reasonably rapid rate of dissolution into water and adequate
water solubility and moderate to low first pass metabolism. A somewhat lower molecular
weight cutoff of 500 daltons (as part of the "rule of five") has been recommended for
oral small molecule drug candidates based on the observation that clinical attrition rates
are significantly reduced if the molecular weight is kept below this limit. [4][5]
Drugs[edit]
Further information: Pharmaceutical drug and Targeted therapy
Most pharmaceuticals are small molecules, although some drugs can be proteins
(e.g., insulin and other biologic medical products). With the exception of therapeutic
antibodies, many proteins are degraded if administered orally and most often cannot
cross cell membranes. Small molecules are more likely to be absorbed, although some
of them are only absorbed after oral administration if given as prodrugs. One advantage
that small molecule drugs (SMDs) have over "large molecule" biologics is that many
small molecules can be taken orally whereas biologics generally require injection or
another parenteral administration.[6]

Secondary metabolites[edit]
A variety of organisms including bacteria, fungi, and plants, produce small
molecule secondary metabolites also known as natural products, which play a role in
cell signaling, pigmentation and in defense against predation. Secondary metabolites
are a rich source of biologically active compounds and hence are often used as
research tools and leads for drug discovery. [7] Examples of secondary metabolites
include:

 Alkaloids
 Glycosides
 Lipids
 Nonribosomal peptides, such as actinomycin-D
 Phenazines
 Natural phenols (including flavonoids)
 Polyketide
 Terpenes, including steroids
 Tetrapyrroles.

Research tools[edit]
Cell culture example of a small molecule as a tool instead of a protein. In cell culture to obtain a pancreatic
lineage from mesodermal stem cells, the retinoic acid signaling pathway must be activated while the sonic
hedgehog pathway inhibited, which can be done by adding to the media anti-shh antibodies, Hedgehog
interacting protein, or cyclopamine, where the first two molecules are proteins and the last a small molecule. [8]

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,
which 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 that activates protein kinase C, which promotes cancer, making it a useful
investigative tool.[9] There is also interest in creating small molecule artificial transcription
factors to regulate gene expression, examples include wrenchnolol (a wrench shaped
molecule).[10]
Binding of ligand can be characterised using a variety of analytical techniques such
as surface plasmon resonance, microscale thermophoresis[11] or dual polarisation
interferometry to quantify the reaction affinities and kinetic properties and also any
induced conformational changes.

Anti-genomic therapeutics[edit]
Small-molecule anti-genomic therapeutics, or SMAT, refers to
a biodefense technology that targets DNA signatures found in many biological
warfare agents. SMATs are new, broad-spectrum drugs that unify antibacterial, antiviral
and anti-malarial activities into a single therapeutic that offers substantial cost benefits
and logistic advantages for physicians and the military. [12]

See also[edit]
 Pharmacology
 Druglikeness
 Lipinski's rule of five
 Metabolite
 Chemogenomics
 Neurotransmitter