Swapnil R. Bhalerao M. Pharm II — Sem. Guided by- Prof. Amrutkar Department of Pharmaceutical Chemistry M. Drug discovery, Design and modification.

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When a lead compound is first discovered for a particular disease state, it often lacks the required potency and pharmacokinetic properties, suitable for making it a viable clinical candidate.

These may include undesirable side effects, physicochemical properties that limit bioavailability, and adverse metabolic or excretion properties. These undesirable properties could be due to specific functional groups present in the molecule. The medicinal chemist therefore must modify the compound to reduce or eliminate these undesirable features without losing the desired biological activity. Replacement or modification of functional groups with other groups having similar properties is known as isosteric or bioisosteric replacement.

In , Langmuir first developed the concept of chemical isosterism to describe the similarities in physical properties among atoms, functional groups, radicals, and molecules. The similarities among atoms described by Langmuir primarily resulted from the fact that these atoms contained the same number of valence electrons and came from the same columns within the periodic table. This concept was limited to elements in adjacent rows and columns, inorganic molecules, ions and small organic molecules such as diazomethane and ketene.

To account for similarities between groups with the same number of valence electrons but different numbers of atoms, Grimm developed his hydride displacement law. However, this is not a "law" in the strict sense, but more of an illustration of similar physical properties among closely related functional groups. The table below presents an example of hydride displacement. Descending diagonally from left to right in the table H atoms are progressively added to maintain the same number of valence electrons for each group of atoms within a column.

Within each column the groups are considered to be "pseudo atoms" with respect to one another. Thus, NH2 is considered to be isosteric to OH, etc. This early view of isosterism did not consider the actual location, motion, and resonance of electrons within the orbitals of these functional group replacements.

Careful observation of this table reveals that some groups do share similar physical and chemical properties, but others have very different properties despite having the same number of valence electrons. For example, OH and NH2 do share similar hydrogen bonding properties and should therefore be interchangeable if that is the only criterion necessary. But, the NH2 is basic whereas the OH is neutral. Hence, at physiological pH the NH2 group would impart a positive charge to the molecule.

If OH is being substituted by NH2 the additional positive charge could have a significant effect on the overall physico-chemical properties of the molecule in which it is being introduced. In addition to basicity and acidity, this "law" fails to take into account other important physical chemical parameters such as electronegativity, polarizability, bond angles, size, shape of molecular orbitals, electron density, and partition coefficients, all of which contribute significantly to the overall physicochemical properties of a molecule.

Instead of considering only partial structures Hinsberg applied the concept of isosterism to entire molecules. He developed the concept of "ring equivalents"; groups that can be exchanged for one another in aromatic ring systems without drastic changes in physico-chemical properties relative to the parent structure.

Benzene, thiophene and pyridine illustrate this concept see figure below. The physical properties of benzene and thiophene are very similar. For example, the boiling point of benzene is Pyridine, however, deviates with a boiling point of C.

Note that hydrogen atoms are ignored in this comparison. Today this isosteric relationship is seen in many drugs. Bioisosterism It is difficult to relate biological properties to physicochemical properties of individual atoms, functional groups or entire molecules because many physical and chemical parameters are involved simultaneously and are therefore difficult to quantitate.

Simple relationships as described above often do not hold up across the many types of biological systems seen with medicinal agents. That is, what may work as an isosteric replacement in one biological system or a given drug receptor may not in another.

Because of this, it was necessary to introduce the term "bioisosterism" to describe functional groups related in structure and having similar biologica effects. Friedman introduced the term bioisosterism and defined it as: "Bioisosteres are functional groups or molecules that have chemical and physical similarities producing broadly similar biological properties. Bioisosteric compounds affect the same biochemically associated systems as agonist or antagonists and thereby produce biological properties that are related to each other.

What may work as a bioisosteric group in one biological system or receptor may not have similar effects on another. Classical and Nonclassical Bioisosteres Bioisosteric groups can be subdivided into two categories: Classical and nonclassical bioisosteres. Functional groups that satisfy the original conditions of Langmuir and Grimm are referred to as classical bioisosteres.

Nonclassical bioisosteres do not obey steric and electronic definitions of classical bioisoteres and do not necessarily have the same number of atoms as the substituent they replace.

A wider set of compounds and functional groups are encompassed by nonclassical bioisoteres which produce, at the molecular level, qualitatively similar agonist or antagonist responses. In animals, many hormones, neurotransmitters etc. An example would be the insulins isolated from various mammalian species. Even though these insulins may differ by several amino acid residues, they still produce the same biological effects.

If this did not occur, the use of insulin to treat diabetes would have had to wait another 60 years for recombinant DNA technology to allow production of human insulin. What maybe a successful bioisosteric replacement for a given molecule interacting with a particular receptor in one instance quite often has no activity, or abolishes biologica activity in another system. Thus, the use of bioisosteric replacement classical or nonclassical in drug design is highly dependent upon the biological system being investigated.

No hard and fast rules exist to determine what bioisosteric replacement is going to work with a given molecule, although as the following tables and examples demonstrate, some generalizations have been possible.

However, the medicinal chemist still must rely on experience and intuition in order to decide the best approach to be used when applying this strategy. Classical bioisosteres can be further subdivided as shown below, and examples are provided in the Table that follows A.



Classical bioisosteres[ edit ] Classical bioisosterism was originally formulated by James Moir and refined by Irving Langmuir [2] as a response to the observation that different atoms with the same valence electron structure had similar biological properties. For example, the replacement of a hydrogen 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. Procainamide , an amide , has a longer duration of action than Procaine , an ester , because of the isosteric replacement of the ester oxygen with a nitrogen atom. Another example are chalcones bioisosteres.


Isosterism and Bioisosterism




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