Molecular modification is chemical alteration of a known and previously characterized lead compound for the purpose of enhancing its usefulness as a drug.
The incorporation of acidic residues into a lead structure is less likely to change the type of activity, but it can result in the analogue exhibiting haemolytic properties.
Basic water solubilizing groups have a tendency to change the mode of action, since bases often interfere with neurotransmitters and biological processes involving amines.
In order to preserve the type of activity exhibited by the lead compound, the water solubilizing group should be attached to a part of the structure that is not involved in the drug–receptor interaction.
Consequently, the route used to introduce a new water solubilizing group and its position in the lead structure will depend on the relative reactivities of the pharmacophore and the rest of the molecule.
Many of these routes require the use of protecting agents to prevent unwanted reactions of either the water solubilizing group or the lead structure.