Inmolecular biology andpharmacology, asmall molecule ormicromolecule is a low molecular weight (≤ 1000daltons[1])organic compound that may regulate a biological process, with a size on the order of 1 nm[citation needed]. Manydrugs are small molecules; the terms are equivalent in the literature.Larger structures such asnucleic acids andproteins, and manypolysaccharides 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 probebiological function as well asleads in the development of newtherapeutic agents. Some can inhibit a specific function of a protein or disruptprotein–protein interactions.[2]
Pharmacology usually restricts the term "small molecule" to molecules that bind specific biologicalmacromolecules and act as aneffector, altering the activity or function of thetarget. Small molecules can have a variety of biological functions or applications, serving ascell signaling molecules,drugs inmedicine,pesticides in farming, and in many other roles. These compounds can be natural (such assecondary metabolites) or artificial (such asantiviral drugs); they may have a beneficial effect against a disease (such asdrugs) or may be detrimental (such asteratogens andcarcinogens).
The uppermolecular-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 reachintracellular sites of action.[1][3] This molecular weight cutoff is also a necessary but insufficient condition for oralbioavailability as it allows fortranscellular transport through intestinalepithelial cells. In addition to intestinal permeability, the molecule must also possess a reasonably rapidrate of dissolution into water and adequate watersolubility and moderate to lowfirst 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]
Most pharmaceuticals are small molecules, although some drugs can be proteins (e.g.,insulin and otherbiologic medical products). With the exception oftherapeutic antibodies, many proteins are degraded if administered orally and most often cannot crosscell membranes. Small molecules are more likely to be absorbed, although some of them are only absorbed after oral administration if given asprodrugs. One advantage thatsmall molecule drugs (SMDs) have over "large molecule"biologics is that many small molecules can be taken orally whereas biologics generally require injection or anotherparenteral administration.[6] Small molecule drugs are also typically simpler to manufacture and cheaper for the purchaser. A downside is that not all targets are amenable to modification with small-molecule drugs; bacteria andcancers are often resistant to their effects.[7]
A variety of organisms including bacteria, fungi, and plants, produce small moleculesecondary metabolites also known asnatural 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.[8] Examples of secondary metabolites include:
Enzymes and receptors are often activated or inhibited byendogenous protein, but can be also inhibited by endogenous or exogenoussmall molecule inhibitors oractivators, which can bind to theactive site or on theallosteric site.
An example is the teratogen and carcinogenphorbol 12-myristate 13-acetate, which is a plant terpene that activatesprotein kinase C, which promotes cancer, making it a useful investigative tool.[10] There is also interest in creating small moleculeartificial transcription factors to regulategene expression, examples include wrenchnolol (a wrench shaped molecule).[11]
Binding ofligand can be characterised using a variety of analytical techniques such assurface plasmon resonance,microscale thermophoresis[12] ordual polarisation interferometry to quantify the reaction affinities and kinetic properties and also any inducedconformational changes.
Small-moleculeanti-genomic therapeutics, or SMAT, refers to abiodefense technology that targetsDNA signatures found in manybiological 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.[13]
The majority of [oral] drugs from the general reference set have molecular weights below 550. In contrast the molecular-weight distribution of oral antibacterial agents is bimodal: 340–450 Da but with another group in the 700–900 molecular weight range.
Table 5.13: Route of Administration: Small Molecules: oral administration usually possible; Biomolecules: Usually administered parenterally