bloodstream, and transport to the liver where it finally reaches the enzyme
HMG-CoA reductase anchored in the membrane of the endoplasmic reticulum.
For this to happen, an oral small-molecule drug – and in fact, the large majority of
marketed drugs are given by the oral route for ease of administration and patient
compliance – needs to combine two important features: aqueous solubility and
membrane permeability. Unfortunately, these two properties work in opposite directions insofar as solubility increases with decreasing logP (and MW) while the
crossing of biological membrane composed of lipid bilayers is facilitated with
increasing logP. Consequently, optimization of compound properties during the
drug discovery phase always has a close eye on the lipophilicity. Moving too far
away from the drug-like space increases the risk of acquiring suboptimal pharmacokinetic properties. For instance, very polar drugs (logP < 0) suffer from poor
absorption, while very lipophilic ones (logP > 5) are poorly soluble in the aqueous
environment of the gastrointestinal tract and are likely to display poor absorption
behavior. As a general rule, a logP in the range of 1–3 is considered a good
compromise for oral small-molecule drugs.
As far as the molecular weight is concerned, for an efficient interaction of a drug
molecule with its target receptor, as thus its potency, specific structural elements and
functional groups are necessary, which in the end determine the size of the molecule.
With increasing molecular weight, however, organic drug-like molecules tend to
gain in lipophilicity, which compromises water solubility [5]. To render large
molecules more soluble, medicinal chemists can introduce functional groups or
motifs that enhance their polarity, be it by adding polar functionalities (hydroxyl
or amino group) or by substituting lipophilic building blocks through closely related
more polar motifs of similar size and shape (phenyl ring to N-heterocycle switch).
Again, such modifications need to be considered with caution because too much
polarity in a large molecule, computed as topological polar surface area (TPSA), is
detrimental to its ability of passively diffusing through biological membranes. Taken
together, finding the right balance in compound structure and properties to satisfy the
requirements in potency, membrane permeability, and water solubility eventually
defines the chemical space: the majority of oral drugs have a logD 0–4 and a
molecular weight of 200–500 Da [6].
Regarding the ion class [7], selection of one type or the other may be dictated by
the preference of the receptor for ligands with specific functional groups. For
instance, the serotonin re-uptake inhibitor sertraline competes with the endogenous
ligand for its binding site on the neuron. Hence, designing a drug with a basic center
to displace the likewise basic natural binding partner of the 5-HT receptor is a way of
building in affinity toward the target. It is worth stressing that ion class has a direct
impact on the three important inherent compound properties: lipophilicity, water
solubility, and membrane permeability. Functional groups that are ionized at physiological pH to a significant extent – mostly basic amines with basicity constants
(pK b ) above 8 and carboxylic acid-bearing compounds with acidity constants (pK a )
typically below 4.5 – cause a reduction of the logP, i.e., the logD as a more
physiologically relevant measure of lipophilicity is shifted to lower values. While
this benefits their water solubility (with the exception of the acidic environment of
The Journey of Human Drugs from Their Design at the Bench to Their Fate in Crops
9
HMG-CoA reductase anchored in the membrane of the endoplasmic reticulum.
For this to happen, an oral small-molecule drug – and in fact, the large majority of
marketed drugs are given by the oral route for ease of administration and patient
compliance – needs to combine two important features: aqueous solubility and
membrane permeability. Unfortunately, these two properties work in opposite directions insofar as solubility increases with decreasing logP (and MW) while the
crossing of biological membrane composed of lipid bilayers is facilitated with
increasing logP. Consequently, optimization of compound properties during the
drug discovery phase always has a close eye on the lipophilicity. Moving too far
away from the drug-like space increases the risk of acquiring suboptimal pharmacokinetic properties. For instance, very polar drugs (logP < 0) suffer from poor
absorption, while very lipophilic ones (logP > 5) are poorly soluble in the aqueous
environment of the gastrointestinal tract and are likely to display poor absorption
behavior. As a general rule, a logP in the range of 1–3 is considered a good
compromise for oral small-molecule drugs.
As far as the molecular weight is concerned, for an efficient interaction of a drug
molecule with its target receptor, as thus its potency, specific structural elements and
functional groups are necessary, which in the end determine the size of the molecule.
With increasing molecular weight, however, organic drug-like molecules tend to
gain in lipophilicity, which compromises water solubility [5]. To render large
molecules more soluble, medicinal chemists can introduce functional groups or
motifs that enhance their polarity, be it by adding polar functionalities (hydroxyl
or amino group) or by substituting lipophilic building blocks through closely related
more polar motifs of similar size and shape (phenyl ring to N-heterocycle switch).
Again, such modifications need to be considered with caution because too much
polarity in a large molecule, computed as topological polar surface area (TPSA), is
detrimental to its ability of passively diffusing through biological membranes. Taken
together, finding the right balance in compound structure and properties to satisfy the
requirements in potency, membrane permeability, and water solubility eventually
defines the chemical space: the majority of oral drugs have a logD 0–4 and a
molecular weight of 200–500 Da [6].
Regarding the ion class [7], selection of one type or the other may be dictated by
the preference of the receptor for ligands with specific functional groups. For
instance, the serotonin re-uptake inhibitor sertraline competes with the endogenous
ligand for its binding site on the neuron. Hence, designing a drug with a basic center
to displace the likewise basic natural binding partner of the 5-HT receptor is a way of
building in affinity toward the target. It is worth stressing that ion class has a direct
impact on the three important inherent compound properties: lipophilicity, water
solubility, and membrane permeability. Functional groups that are ionized at physiological pH to a significant extent – mostly basic amines with basicity constants
(pK b ) above 8 and carboxylic acid-bearing compounds with acidity constants (pK a )
typically below 4.5 – cause a reduction of the logP, i.e., the logD as a more
physiologically relevant measure of lipophilicity is shifted to lower values. While
this benefits their water solubility (with the exception of the acidic environment of
The Journey of Human Drugs from Their Design at the Bench to Their Fate in Crops
9