Bioisostere
Encyclopedia
In medicinal chemistry
, bioisosteres are substituent
s or groups with similar physical or chemical properties which produce broadly similar biological properties to a chemical compound. In drug design
, the purpose of exchanging one bioisostere for another is to enhance the desired biological or physical properties of a compound without making significant changes in chemical structure. The main use of this term and it techniques are related to pharmaceutical sciences. Bioisosterism is used to reduce toxicity or modify the activity of the lead compound, and may alter the metabolism of the lead.
atom with a fluorine
atom at a site of metabolic oxidation
in a drug candidate may prevent such metabolism from taking place. Because the fluorine atom is similar in size to the hydrogen atom the overall topology of the molecule is not significantly affected, leaving the desired biological activity unaffected. However, with a blocked pathway for metabolism, the drug candidate may have a longer half-life.
There are many examples of bioisosteres, which may be equivalent in some instances but not in others depending on what factors are important in binding (electronegativity, size, polarity etc.). So for instance a chlorine -Cl group may often be replaced by a trifluoromethyl -CF3 group, or by a cyano -C≡N group, but depending on the particular molecule used the substitution may result in little change in activity, or either increase or decrease affinity or efficacy depending on what factors are important for target binding. Another example is aromatic rings, a phenyl -C6H5 ring can often be replaced by a different aromatic ring such as thiophene
or naphthalene
which may either improve efficacy or change specificity of binding.
Medicinal chemistry
Medicinal chemistry and pharmaceutical chemistry are disciplines at the intersection of chemistry, especially synthetic organic chemistry, and pharmacology and various other biological specialties, where it is involved with design, chemical synthesis and development for market of pharmaceutical...
, bioisosteres are substituent
Substituent
In organic chemistry and biochemistry, a substituent is an atom or group of atoms substituted in place of a hydrogen atom on the parent chain of a hydrocarbon...
s or groups with similar physical or chemical properties which produce broadly similar biological properties to a chemical compound. In drug design
Drug design
Drug design, also sometimes referred to as rational drug design or structure-based drug design, is the inventive process of finding new medications based on the knowledge of the biological target...
, the purpose of exchanging one bioisostere for another is to enhance the desired biological or physical properties of a compound without making significant changes in chemical structure. The main use of this term and it techniques are related to pharmaceutical sciences. Bioisosterism is used to reduce toxicity or modify the activity of the lead compound, and may alter the metabolism of the lead.
Examples
For example, the replacement of a hydrogenHydrogen
Hydrogen is the chemical element with atomic number 1. It is represented by the symbol H. With an average atomic weight of , hydrogen is the lightest and most abundant chemical element, constituting roughly 75% of the Universe's chemical elemental mass. Stars in the main sequence are mainly...
atom with a fluorine
Fluorine
Fluorine is the chemical element with atomic number 9, represented by the symbol F. It is the lightest element of the halogen column of the periodic table and has a single stable isotope, fluorine-19. At standard pressure and temperature, fluorine is a pale yellow gas composed of diatomic...
atom at a site of metabolic oxidation
Metabolism
Metabolism is the set of chemical reactions that happen in the cells of living organisms to sustain life. These processes allow organisms to grow and reproduce, maintain their structures, and respond to their environments. Metabolism is usually divided into two categories...
in a drug candidate may prevent such metabolism from taking place. Because the fluorine atom is similar in size to the hydrogen atom the overall topology of the molecule is not significantly affected, leaving the desired biological activity unaffected. However, with a blocked pathway for metabolism, the drug candidate may have a longer half-life.
- ProcainamideProcainamideProcainamide INN is a pharmaceutical antiarrhythmic agent used for the medical treatment of cardiac arrhythmias, classified by the Vaughan Williams classification system as class Ia.-History:...
, an amideAmideIn chemistry, an amide is an organic compound that contains the functional group consisting of a carbonyl group linked to a nitrogen atom . The term refers both to a class of compounds and a functional group within those compounds. The term amide also refers to deprotonated form of ammonia or an...
, has a longer duration of action than ProcaineProcaineProcaine is a local anesthetic drug of the amino ester group. It is used primarily to reduce the pain of intramuscular injection of penicillin, and it was also used in dentistry. Owing to the ubiquity of the trade name Novocain, in some regions procaine is referred to generically as novocaine...
, an esterEsterEsters are chemical compounds derived by reacting an oxoacid with a hydroxyl compound such as an alcohol or phenol. Esters are usually derived from an inorganic acid or organic acid in which at least one -OH group is replaced by an -O-alkyl group, and most commonly from carboxylic acids and...
, because of the isosteric replacement of the ester oxygenOxygenOxygen is the element with atomic number 8 and represented by the symbol O. Its name derives from the Greek roots ὀξύς and -γενής , because at the time of naming, it was mistakenly thought that all acids required oxygen in their composition...
with a nitrogenNitrogenNitrogen is a chemical element that has the symbol N, atomic number of 7 and atomic mass 14.00674 u. Elemental nitrogen is a colorless, odorless, tasteless, and mostly inert diatomic gas at standard conditions, constituting 78.08% by volume of Earth's atmosphere...
atom. - Alloxanthine is an inhibitor of xanthine oxidaseXanthine oxidaseXanthine oxidase Xanthine oxidase Xanthine oxidase (XO (sometimes 'XAO'), a form of xanthine oxidoreductase that generates reactive oxygen species. Is an enzyme that catalyzes the oxidation of hypoxanthine to xanthine and can further catalyze the oxidation of xanthine to uric acid...
. It is also an isostere of XanthineXanthineXanthine , is a purine base found in most human body tissues and fluids and in other organisms. A number of stimulants are derived from xanthine, including caffeine and theobromine....
, the normal substrate for the enzymeEnzymeEnzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
.
There are many examples of bioisosteres, which may be equivalent in some instances but not in others depending on what factors are important in binding (electronegativity, size, polarity etc.). So for instance a chlorine -Cl group may often be replaced by a trifluoromethyl -CF3 group, or by a cyano -C≡N group, but depending on the particular molecule used the substitution may result in little change in activity, or either increase or decrease affinity or efficacy depending on what factors are important for target binding. Another example is aromatic rings, a phenyl -C6H5 ring can often be replaced by a different aromatic ring such as thiophene
Thiophene
Thiophene is a heterocyclic compound with the formula C4H4S. Consisting of a flat five-membered ring, it is aromatic as indicated by its extensive substitution reactions. Related to thiophene are benzothiophene and dibenzothiophene, containing the thiophene ring fused with one and two benzene...
or naphthalene
Naphthalene
Naphthalene is an organic compound with formula . It is a white crystalline solid with a characteristic odor that is detectable at concentrations as low as 0.08 ppm by mass. As an aromatic hydrocarbon, naphthalene's structure consists of a fused pair of benzene rings...
which may either improve efficacy or change specificity of binding.