3 Physico-chemical Space of Small-Molecule Drugs
With the exclusive coverage of small-molecule drugs in this book, the focus of this
section is on the 3,000+ substances with marketing approval. The physico-chemical
space they occupy can be defined by three simple, and experimentally readily
accessible, properties, namely, molecular weight (MW), lipophilicity, and ion
class. While the molecular weight is derived directly from the elemental formula,
lipophilicity is commonly measured as the partition coefficient of the compound
between n-octanol and water (yielding logP for neutral species or the pH-dependent
logD for charged species). The ion class reflects the presence of functional groups in
the chemical structure that are ionizable at physiological pH, e.g., the carboxylic
acid-bearing anti-inflammatory drug diclofenac belongs the group of acids, whereas
the aliphatic amine in the antidepressant sertraline acts as a basic center amenable to
protonation. The modern cookbook of the medicinal chemist is replete of synthetic
approaches to design virtually any organic molecule; but what are his/her criteria in
the search for the right spot in the three-dimensional space? The answer lies first and
foremost at the molecular level in the binding of the molecule to the receptor whose
physiological function he/she set out to modulate in the belief that this ultimately
translates into the desired pharmacological response in humans. For this binding to
take place, the drug molecule has to establish a number of specific interactions with
the structural building blocks of the receptor, typically in the form of hydrogen
bonding, van der Waals interactions, and hydrophobic interactions. In case of protein
targets, the drug molecule interacts through its functional groups with the structurally diverse amino acids constituting the protein. The number and strength of
interactions of the molecule with the site of the receptor essential for its physiological function, e.g., the site of the enzyme where its natural ligand binds to, then
determine the thermodynamic association constant, i.e., its potency toward the
target. Tuning these interactions for high affinity toward the selected pharmacological target while minimizing off-target selectivity is the ultimate goal of the synthetic
efforts. When no previous knowledge on the chemical environment of functionaltering site is available in the public domain, screening of chemical libraries is a
commonly applied approach with subsequent optimization of hit compounds in a
trial-and-error mode in order to establish structure-activity relationships. On the
other hand, if the three-dimensional structure of the receptor has been elucidated,
e.g., through X-ray crystallography, and competitor compounds are available, virtual
docking methods can help identify ways to improve the binding of the ligand to the
receptor. Such strategy ultimately yields structurally very similar drugs, which may
exhibit differences in one or several aspects relating to potency, pharmacokinetic
properties, and overall safety and tolerability profiles.
Next to the aforementioned binding criteria, a further key attribute intimately
linked to the physico-chemical properties of the compound is the ability to reach the
target site in amounts sufficient for coverage. For example, atorvastatin contained in
an orally dosed tablet undergoes a sequence of events to reach the site of action:
liberation of the active, dissolution, absorption in the intestine, transfer into the
8
N. Montemurro et al.
With the exclusive coverage of small-molecule drugs in this book, the focus of this
section is on the 3,000+ substances with marketing approval. The physico-chemical
space they occupy can be defined by three simple, and experimentally readily
accessible, properties, namely, molecular weight (MW), lipophilicity, and ion
class. While the molecular weight is derived directly from the elemental formula,
lipophilicity is commonly measured as the partition coefficient of the compound
between n-octanol and water (yielding logP for neutral species or the pH-dependent
logD for charged species). The ion class reflects the presence of functional groups in
the chemical structure that are ionizable at physiological pH, e.g., the carboxylic
acid-bearing anti-inflammatory drug diclofenac belongs the group of acids, whereas
the aliphatic amine in the antidepressant sertraline acts as a basic center amenable to
protonation. The modern cookbook of the medicinal chemist is replete of synthetic
approaches to design virtually any organic molecule; but what are his/her criteria in
the search for the right spot in the three-dimensional space? The answer lies first and
foremost at the molecular level in the binding of the molecule to the receptor whose
physiological function he/she set out to modulate in the belief that this ultimately
translates into the desired pharmacological response in humans. For this binding to
take place, the drug molecule has to establish a number of specific interactions with
the structural building blocks of the receptor, typically in the form of hydrogen
bonding, van der Waals interactions, and hydrophobic interactions. In case of protein
targets, the drug molecule interacts through its functional groups with the structurally diverse amino acids constituting the protein. The number and strength of
interactions of the molecule with the site of the receptor essential for its physiological function, e.g., the site of the enzyme where its natural ligand binds to, then
determine the thermodynamic association constant, i.e., its potency toward the
target. Tuning these interactions for high affinity toward the selected pharmacological target while minimizing off-target selectivity is the ultimate goal of the synthetic
efforts. When no previous knowledge on the chemical environment of functionaltering site is available in the public domain, screening of chemical libraries is a
commonly applied approach with subsequent optimization of hit compounds in a
trial-and-error mode in order to establish structure-activity relationships. On the
other hand, if the three-dimensional structure of the receptor has been elucidated,
e.g., through X-ray crystallography, and competitor compounds are available, virtual
docking methods can help identify ways to improve the binding of the ligand to the
receptor. Such strategy ultimately yields structurally very similar drugs, which may
exhibit differences in one or several aspects relating to potency, pharmacokinetic
properties, and overall safety and tolerability profiles.
Next to the aforementioned binding criteria, a further key attribute intimately
linked to the physico-chemical properties of the compound is the ability to reach the
target site in amounts sufficient for coverage. For example, atorvastatin contained in
an orally dosed tablet undergoes a sequence of events to reach the site of action:
liberation of the active, dissolution, absorption in the intestine, transfer into the
8
N. Montemurro et al.