Molecular Modification: A Tool for Pruning the Molecule

A. Any alteration in the structure of known and previously characterized molecule for the purpose of enhancing its usefulness as drug is called as Molecular modification [1].
B. Molecules obtained as a result of molecular modification are called as analogues or congeners.
C. The term molecular modification was coined by Hench.
D. It is also called as Molecular refinement, Molecular transformation, Molecular tailoring, Chemical modification, Chemical alteration, Pharmacomodulation and Method of variation.
E. It is one of tools of research in medicinal chemistry to refine molecules [2].
F. Molecular modifications of prototype (original) structures have yielded from no or little to moderate to significant improvements in their pharmacological potency.
G. Molecular modification by nature has been going on since the beginning of life.
H. Chemists have learned from nature about the effect of small changes in the structure of molecule on its biological activity.
I. Most of the molecules are modified either by altering its physical properties or by modifying the chemical structure.

Types of molecular modification

A. Natural: E.g., Morphine-Codeine

B. Synthetic: E.g., Prontosil-Sulfanilamide

Purpose of molecular modification

A. To improve or to alter the pharmacokinetics and Pharmacodynamics of the drug [3].

Criteria for molecular modification

A. The molecule should be a known one.

B. The molecule should be characterized one.

Overview of approaches in molecular modification

Conjunction approach:

A. Molecular addition approach.

B. Molecular replication approach.

C. Molecular hybridization approach.

Disjunction approach:

Special approach:

A. Bio isosteric replacement [4].

B. Homologation [5].

C. Change of position and orientation of some groups.

D. Ring closing or ring opening methods.

Advantages of molecular modification [6]

I. It enhances the selectivity or affinity of drug to a particular biological target.
II. It increases the potency or efficacy of the drug.
III. It improves the rate, extent of absorption and bioavailability of the drug.
IV. It reduces the toxicity of the drug.
V. It instills desired features in the drug.
VI. It improves duration of action of the drug.
VII. It decreases the cost of production of the drug.
VIII. SAR studies of the drug can be undertaken.
IX. It reduces the side effects of the drug.
X. It increases metabolic stability or half-life of the drug.
XI. It improves the overall safety of the drug.
XII. It improves the formulation of the drug.
XIII. It improves the acceptability of the drug by the patient.

Disadvantages of molecular modification

I. It alters the shape of the drug molecule.
II. It alters the solubility of the drug molecule.
III. It may alter the polarity of the drug molecule.
IV. It may alter the flexibility of the drug molecule.
V. It alters the physico-chemical properties of the drug molecule.
VI. It alters the bioactivity of the drug molecule (Table 1).

Table 1: Examples for molecular modification.

Molecular modification is a revolution in contemporary drug development and still a major line of approach for the discovery of new drugs. Molecular modification broadens the scope of usefulness of leads, but one has to be careful in measuring the effect of molecular modification of lead on its potency. To pave the way for future research, there is a need to collect the latest information in this promising area.

Authors are thankful to the General Secretary and the Principal of Vaageswari Institute of Pharmaceutical Sciences for providing the necessary support for the review work.

1. Pandeya SN, Dimmock JR (1997) An Introduction to Drug Design. New Age International, p.27.
2. Max Tishler (1964) Molecular modification in modern drug research. Advances in chemistry 45(1): 1-14.
3. John Gajewski (1965) Modification in drug design. Clinical Chemistry 11(5): 612.
4. Lidia Moreira, Eliezer B (2005) Bioisosterism: A useful strategy for molecular modification and drug design. Current Medicinal Chemistry 12(1): 23-49.
5. Lima LM, Alves MA, Amaral DN (2019) Homologation: A versatile molecular modification strategy to drug discovery. Curr Top Med Chem 19(19): 1734-1750.
6. Richard Silvemann (2015) The organic chemistry of drug design and drug action. (2^nd edn), Elsevier, Amsterdam, Netherlands, p. 21.