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7.5: Molecular Modification

  • Page ID
    233815
  • Once a lead compound or a pharmacophore structure with the desired pharmacological effect has been identified, organic chemists can introduce modifications in the chemical structure of the lead compound with the goal of improving the pharmacokinetics or pharmacodynamics of a drug candidate. These evolved structures are known as analogs. There are two important factors that organic chemist must consider when modifying the chemical structure of a drug candidate which are

    The effect of the chemical modification on polarity and solubility

    The effect of the chemical modification on molecular shape and flexibility


    Molecular shape and flexibility

    The presence of flexible or rigid groups can affect the molecular shape and therefore the ability of the drug to bind a specific ligand in the body. For example,  the introduction of unsaturated groups and ring systems generate more structurally rigid analog than aliphatic systems. Figure 1 shows the structure of dopamine and a more structurally rigid analog.

    Dopamine analogs.png

    Figure 1. Dopamine and an analog with fewer possible conformations due to the ring

    The biological effects induced by changes in the molecular flexibility are difficult to predict. Every single new analog needs to be retested in order to determine its pharmacological properties, and compare them with the lead compound. A more rigid molecule tends to create a stronger binding to its biological target (receptor), However,  when the target receptor has a more flexible binding site, increasing molecular rigidity might decrease the ability of the drug to enter this site. 

    Polarity and Flexibility

    The relative solubility of a drug in both aqueous and non-polar media plays a major role in the ability of the body to absorbe and transport the active molecule to its action site. Most of the time, the drug must be hydrophilic enough to be able transported in the blood, but also lipophilic enough to travel through a membrane.

     

    Dopamine analogs_2.png

    Figure 2. Increased lipophilicity of a dopamine analog by methylation of phenol groups.

     

    We must consider that polarity (and therefore solubility in polar and non-polar media) is a synergistic effect, and it is the combined effect of functional groups and molecular geometry that will determine the polarity of a drug candidate. However, there are certain tendencies that are summarized in table 1. 

    Molecular modifications that increase hydrophilicity Molecular modifications that increase lipophilicity

    -OH

    -NH2

    -COOH

    -SO3H

    salt formation

    -CH3 

    -C(CH3)3

    -F, -Cl, -I

    phenyl

    -COOR (ester)

    As in the case of molecular shape, the introduction of additional functional groups and substituents (chemical modifications) may alter the biological effect of the drug. Every new analog needs to be tested in order to determine its new pharmacological properties (pharmacokinetics and pharmacodynamics). 

    Sources

     

    Thomas, G. (2003). Fundamentals of Medicinal Chemistry (1st ed.). Wiley-Blackwell.

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