Category Archives: Information

Small molecule

In molecular biology and pharmacology, a small molecule is a low molecular weight (<900 Daltons[1]) organic compound that may help regulate a biological process, with a size on the order of 10−9 m. Most drugs are small molecules.

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 they can reach intracellular sites of action.[1][2] In addition, this molecular weight cutoff is a necessary but insufficient condition for oral bioavailability. Finally, a lower molecular weight cutoff of 500 Daltons (as part of the «rule of five») has been recommended for small molecule drug development candidates based on the observation that clinical attrition rates are significantly reduced if the molecular weight is kept below this 500 Dalton limit.[3][4]

Pharmacology usually restricts the term to a molecule that binds to a specific biopolymer—such as protein or nucleic acid—and acts as an effector, altering the activity or function of the biopolymer. Small molecules can have a variety of biological functions, serving as cell signaling molecules, as drugs in medicine, as 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). Biopolymers such as nucleic acids and proteins, and polysaccharides (such as starch or cellulose) are not small molecules—though their constituent monomers—ribo- or deoxyribonucleotides, amino acids, and monosaccharides, respectively—are often considered small molecules. Very small oligomers are also usually considered small molecules, such as dinucleotides, peptides such as the antioxidant glutathione, and disaccharides such as sucrose.

Small molecules may also 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 multifunctional protein or disrupt protein—protein interactions.[5]

An NCE is a molecule developed by the innovator

An NCE is a molecule developed by the innovator company in the early drug discovery stage, which after undergoing clinical trials could translate into a drug that could be a cure for some disease. Synthesis of an NCE is the first step in the process of drug development. Once the synthesis of the NCE has been completed, companies have two options before them. They can either go for clinical trials on their own or license the NCE to another company. In the latter option, companies can avoid the expensive and lengthy process of clinical trials, as the licensee company would be conducting further clinical trials and subsequently launching the drug. Companies adopting this model of business would be able to generate high margins as they get a huge one-time payment for the NCE apart from entering into a revenue sharing agreement with the licensee company.

Proteins are assembled from amino

Proteins are assembled from amino acids using information encoded in genes. Each protein has its own unique amino acid sequence that is specified by the nucleotide sequence of the gene encoding this protein. The genetic code is a set of three-nucleotide sets called codons and each three-nucleotide combination designates an amino acid, for example AUG (adenine-uracil-guanine) is the code for methionine. Because DNA contains four nucleotides, the total number of possible codons is 64; hence, there is some redundancy in the genetic code, with some amino acids specified by more than one codon. Genes encoded in DNA are first transcribed into pre-messenger RNA (mRNA) by proteins such as RNA polymerase. Most organisms then process the pre-mRNA (also known as a primary transcript) using various forms of Post-transcriptional modification to form the mature mRNA, which is then used as a template for protein synthesis by the ribosome. In prokaryotes the mRNA may either be used as soon as it is produced, or be bound by a ribosome after having moved away from the nucleoid. In contrast, eukaryotes make mRNA in the cell nucleus and then translocate it across the nuclear membrane into the cytoplasm, where protein synthesis then takes place. The rate of protein synthesis is higher in prokaryotes than eukaryotes and can reach up to 20 amino acids per second.

Morphine is the most abundant

Morphine is the most abundant opiate found in opium, the dried latex from unripe seedpods of Papaver somniferum (the opium poppy). Morphine was the first active ingredient purified from a plant source. It is one of at least fifty alkaloids of several different types present in opium, poppy straw concentrate, and other poppy derivatives. The primary source of morphine is chemical extraction from opium.

Proteins are the chief actors

Proteins are the chief actors within the cell, said to be carrying out the duties specified by the information encoded in genes. With the exception of certain types of RNA, most other biological molecules are relatively inert elements upon which proteins act. Proteins make up half the dry weight of an Escherichia coli cell, whereas other macromolecules such as DNA and RNA make up only 3% and 20%, respectively. The set of proteins expressed in a particular cell or cell type is known as its proteome.

Morphine was first isolated

Morphine was first isolated in 1804 by Friedrich Sertürner, which is generally believed to be the first ever isolation of a natural plant alkaloid in history. Sertürner began distributing it in 1817, and Merck began marketing it commercially in 1827. At the time, Merck was a single small chemists’ shop. Morphine was more widely used after the invention of the hypodermic needle in 1857. Sertürner originally named the substance morphium after the Greek god of dreams, Morpheus (Greek: ΜορφεПЌς), for its tendency to cause sleep. It is on the World Health Organization’s List of Essential Medicines, a list of the most important medication needed in a basic health system.

The chief characteristic of proteins

The chief characteristic of proteins that also allows their diverse set of functions is their ability to bind other molecules specifically and tightly. The region of the protein responsible for binding another molecule is known as the binding site and is often a depression or «pocket» on the molecular surface. This binding ability is mediated by the tertiary structure of the protein, which defines the binding site pocket, and by the chemical properties of the surrounding amino acids’ side chains. Protein binding can be extraordinarily tight and specific; for example, the ribonuclease inhibitor protein binds to human angiogenin with a sub-femtomolar dissociation constant (<10−15 M) but does not bind at all to its amphibian homolog onconase (>1 M). Extremely minor chemical changes such as the addition of a single methyl group to a binding partner can sometimes suffice to nearly eliminate binding; for example, the aminoacyl tRNA synthetase specific to the amino acid valine discriminates against the very similar side chain of the amino acid isoleucine.

The effects of morphine can be countered

The effects of morphine can be countered with opioid antagonists such as naloxone and naltrexone; the development of tolerance to morphine may be inhibited by NMDA antagonists such as ketamine or dextromethorphan. The rotation of morphine with chemically dissimilar opioids in the long-term treatment of pain will slow down the growth of tolerance in the longer run, particularly agents known to have significantly incomplete cross-tolerance with morphine such as levorphanol, ketobemidone, piritramide, and methadone and its derivatives; all of these drugs also have NMDA antagonist properties. It is believed that the strong opioid with the most incomplete cross-tolerance with morphine is either methadone or dextromoramide.

Chemical library

A chemical library or compound library is a collection of stored chemicals usually used ultimately in high-throughput screening or industrial manufacture. The chemical library can consist in simple terms of a series of stored chemicals. Each chemical has associated information stored in some kind of database with information such as the chemical structure, purity, quantity, and physiochemical characteristics of the compound.

In drug discovery high-throughput screening, it is desirable to screen a drug target against a selection of chemicals that try to take advantage of as much of the appropriate chemical space as possible. The chemical space of all possible chemical structures is extraordinarily large. Most stored chemical libraries do not typically have a fully represented or sampled chemical space mostly because of storage and cost concerns. However, since many molecular interactions cannot be predicted, the wider the chemical space that is sampled by the chemical library, the better the chance that high-throughput screening will find a «hit» — a chemical with an appropriate interaction in a biological model that might be developed into a drug.

An example of a chemical library in drug discovery would be a series of chemicals known to inhibit kinases, or in industrial processes, a series of catalysts known to polymerize resins.

Morphine has long been known

Morphine has long been known to act on receptors expressed on cells of the central nervous system resulting in pain relief and analgesia. In the 1970s and ’80s, evidence suggesting that opiate drug addicts show increased risk of infection (such as increased pneumonia, tuberculosis, and HIV) led scientists to believe that morphine may also affect the immune system. This possibility increased interest in the effect of chronic morphine use on the immune system.