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).
Molecular weight cutoff
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]
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] 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 and cancers are often resistant to their effects.[7]
Secondary metabolites
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.[8] Examples of secondary metabolites include:
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.[13]
^ abMacielag MJ (2012). "Chemical properties of antibacterials and their uniqueness". In Dougherty TJ, Pucci MJ (eds.). Antibiotic Discovery and Development. Springer. pp. 801–2. ISBN978-1-4614-1400-1. 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.
^Arkin MR, Wells JA (April 2004). "Small-molecule inhibitors of protein-protein interactions: progressing towards the dream". Nature Reviews Drug Discovery. 3 (4): 301–17. doi:10.1038/nrd1343. PMID15060526. S2CID13879559.
^Veber DF, Johnson SR, Cheng HY, Smith BR, Ward KW, Kopple KD (June 2002). "Molecular properties that influence the oral bioavailability of drug candidates". J. Med. Chem. 45 (12): 2615–23. CiteSeerX10.1.1.606.5270. doi:10.1021/jm020017n. PMID12036371.
^Lipinski CA (December 2004). "Lead-and drug-like compounds: the rule-of-five revolution". Drug Discovery Today: Technologies. 1 (4): 337–341. doi:10.1016/j.ddtec.2004.11.007. PMID24981612.
^Leeson PD, Springthorpe B (November 2007). "The influence of drug-like concepts on decision-making in medicinal chemistry". Nature Reviews Drug Discovery. 6 (11): 881–90. doi:10.1038/nrd2445. PMID17971784. S2CID205476574.
^Samanen J (2013). "Chapter 5.2 How do SMDs differ from biomolecular drugs?". In Ganellin CR, Jefferis R, Roberts SM (eds.). Introduction to Biological and Small Molecule Drug Research and Development: theory and case studies (Kindle ed.). New York: Academic Press. pp. 161–203. doi:10.1016/B978-0-12-397176-0.00005-4. ISBN978-0-12-397176-0. Table 5.13: Route of Administration: Small Molecules: oral administration usually possible; Biomolecules: Usually administered parenterally