Course Title: Computer Aided Drug Design

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 Bioisosterism
• Lead identification and Optimization

• Lead compound often lacks required potency and pharmacokinetic properties for
making it a viable clinical candidate

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• It includes undesirable side effects, oral biovailability, adverse metabolic or excretion

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properties

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• Replacement or modification of specific functions groups with other groups having

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similar properties is called isosteric replacement or bioisosteric replacement

• In 1919, Langmuir first developed the concept of chemical isosterism to describe the
similarities in properties among atoms or groups
 Bioisosterism
• Fact is primarily from atoms containing same number of valence electrons or from
same columns of periodic table

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 Bioisosterism
• Grimm- similarities between groups with same number of valence electrons but
different number of atoms

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 Bioisosterism
• Some of them share similar properties and are interchangeable

• Like OH and NH2, share similar hydrogen bonding properties

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• But NH2 is basic- exists in protonated form and OH is neutral

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• Replacement of OH will improve physicochemical properties

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• -CH3 relative to OH and –NH2 is still greater

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 Bioisosterism
• Hinsberg- applied concept of isosterism to entire molecules

• Ring equivalents

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• Functional groups can be exchanged from one another in aromatic systems without

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drastic changes in physicochemical properties

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 Bioisosterism
• Benzene, pyridine, thiophene- similar concept

• Properties of benzene and thiophene are similar

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• Hinsberg concluded that –C=C- and S are isosteric

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• It is difficult to relate biological activity and physicochemical properties

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• Friedman- Bioisosteres are groups or molecules having chemical and physical

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similarities producing broadly similar biological properties

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• Burger expanded to- Bioisosteres are compounds or groups that possess near equal
molecular shapes and volumes, similar distribution of electrons and exhibit similar
properties
 Bioisosterism
• Further classified to classical and non-classical bioisosteres

• Classical- functional groups that satisfy conditions of Langmuir and Grimm

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• Non-classical- do not obey definitions and do not have same number of atoms

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• Wider set of compounds and functional groups comes under the class of non-

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classical

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Classical Bioisosterers
Non-classical Bioisosterers

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 Case study-1
• When a group is present in a part of a molecule in which it may be involved in an
essential interaction or may influence the reactions of neighboring groups, isosteric

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replacement sometimes produces analogs that act as antagonists

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• The 6-NH2 and 6-OH groups appear to play essential roles in the hydrogen bonding

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interactions of base pairs during nucleic acid replication in cells

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• Adenine, hypoxanthine and the antineoplastic 6-mercaptopurine

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• Illustrate how substitution of the significantly weaker hydrogen-bonding isosteric
sulfhydryl groups results in a partial blockage of this interaction and a decrease in the
rate of cellular synthesis
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 Case study-2
• Replacement of the hydroxyl group of pteroylglutamic acid (folic acid) by the isosteric
amino group and addition of the methyl group to the p-aminobenzoate leads to the

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widely used methotrexate, a folate antimetabolite

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 Case study-3
• Replacement of the hydrogen at the 5-position of uracil with the isosteric fluorine
producing 5-fluorouracil blocks the methylation step leading to thymine

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