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194 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
interactions, they have the ability to provide a much greater bond energy than the dipole–dipole
interactions previously discussed. Electron rich aromatic rings include five-membered aromatic heterocyclic rings and phenyl rings that have electron donating functional groups (Figure 6-24). Similar
to an unsubstituted phenyl ring, pyrrole, furan, and thiophene, have six π electrons; however, the
π electrons in these latter three rings are delocalized over five atoms instead of six. Thus, compared with an unsubstituted phenyl ring, pyrrole, furan, and thiophene are electron rich. This concept is also applicable for other five-membered heterocyclic rings and five-six fused, bicyclic rings.
Examples of these are shown in Figure 6-24. The addition of an electron donating group to a phenyl
ring enhances the electron density of the ring and makes it electron rich. Functional groups that can
donate electrons through resonance, such as an amine, an ether, or a hydroxyl group, can provide a
greater effect than those that can only donate through induction, such as an alkyl group.
FIGURE 6-24.Examples of electron rich aromatic rings.
Electron deficient, or electron poor, aromatic rings include six-membered aromatic heterocyclic
rings and phenyl rings that have electron withdrawing functional groups (Figure 6-25). Six-membered
aromatic heterocycles, such as pyridine, pyrimidine, pyridazine, and pyrazine, are electron poor due
to the electronegativity of the nitrogen atoms. The higher electronegativity of the nitrogen atoms
draws the π electrons toward them and away from the other carbon atoms. This unequal sharing
of electrons causes the aromatic ring as a whole to be electron deficient. This concept extends to
six-six fused, bicyclic rings such as quinolone, quinazoline, and pteridine. The addition of an electron
withdrawing group to a phenyl ring decreases the electron density of the ring and makes it electron
deficient. Similar to what is seen with electron donating functional groups, those that can withdraw
electrons through resonance, such as a nitrile, nitro, or a carbonyl group, can provide a greater effect
than those that can only withdraw through induction, such as halogen.
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FIGURE 6-25.Examples of electron deficient aromatic rings.
An example of a charge transfer reaction is shown in Figure 6-26 with nefazodone, an antidepressant drug that acts as an antagonist at serotonin 5-HT2 postsynaptic receptors. The chloro substituted phenyl ring is electron deficient and could form a charge transfer reaction with an electron
rich tryptophan residue within the 5-HT2 postsynaptic receptor binding site.
FIGURE 6-26.Example of a charge transfer interaction.
Summary of Biological Targets and Drug Binding Interactions
As mentioned at the beginning of this chapter, the primary biological targets for drug molecules are
proteins and nucleic acids. Throughout this chapter, various examples have been used to emphasize
the possible types of binding interactions that can occur between these major biological targets and
196 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
the functional groups within the structure of a drug molecule. To aid in future application of these
concepts, Table 6-4 has been developed to provide a summary of the types of binding interactions
that are possible for amino acids and nucleic acids.
TABLE 6-4.Summary of Binding Interactions for Amino Acids and
Nucleic Acids at Physiologic pH
Side Chain Functional
Amino Acid
Aspartic acid and
Glutamic Acid
Asparagine and
Glutamine
Lysine Primary amine
Arginine Guanidine (basic) Ionic, reinforced ionic, ion-dipole (as the ion),
Histidine Imidazole ring (basic) If ionized: Ionic, reinforced ionic, ion-dipole (as the
Serine and Threonine Primary hydroxyl Dipole-dipole, hydrogen bond (as either donor or
Tyrosine Phenolic aromatic ring Phenol (aromatic hydroxyl): Dipole-dipole, hydrogen
Phenylalanine Aromatic ring van der Waals, hydrophobic, π−π stacking, cation-π
Tryptophan Aromatic ring (indole) van der Waals, hydrophobic, π−π stacking, charge
Cysteine Sulfhydryl Dipole-dipole, hydrogen bond (as either donor or
Methionine Thioether Hydrogen-bond (as an acceptor), van der Waals,
Alanine, Valine, Leucine,
Isoleucine, and Proline
Glycine Hydrogen atom None
a
Group
Carboxylic acid
(acidic)
b
Amide
(basic)
Hydrocarbon van der Waals, hydrophobic
Types of Possible Binding Interactions at pH = 7.4
Ionic, reinforced ionic, ion-dipole (as the ion)
Dipole-dipole, hydrogen bond (as either donor or
acceptor), ion-dipole (as the dipole)
Ionic, reinforced ionic, ion-dipole (as the ion),
cation-π (as the cation)
cation-π (as the cation)
ion), cation-π (as the cation)
If unioinized: Dipole-dipole, hydrogen bond (as
either donor or acceptor), ion-dipole (as the dipole)
acceptor), ion-dipole (as the dipole)
bond (as either donor or acceptor), ion-dipole (as
the dipole)
Aromatic Ring: van der Waals, hydrophobic, π−π
stacking, charge transfer (electron rich), cation-π
(as the π -cloud)
(as the π -cloud)
transfer (electron rich), cation-π (as the π -cloud),
hydrogen bond (as the donor)
acceptor)
hydrophobic
Nucleic Acid Component Functional Group Types of Possible Binding Interactions at pH = 7.4
Purine and Pyrimidine
Rings
Sugar (ribose or
deoxyribose)
Phosphate Phosphate (acidic) Ionic, reinforced ionic, ion-dipole (as the ion)
a
This excludes the carboxylic acid and primary amine present on every amino acid because they would be
involved in peptide bonds.
b
The peptide bond (or amide) could participate in the same types of binding interactions.
Heterocylic, substituted
aromatic rings
Hydroxyl group,
hemiacetal oxygen
atom
π−π Stacking, hydrophobic, hydrogen bonds (as
either donor or acceptor), dipole-dipole
Hydroxyl group: Hydrogen bonds (as either donor or
acceptor), dipole-dipole, ion-dipole (as the dipole)
Hemiacetal oxygen: Same as hydroxyl, but only a
hydrogen bond acceptor
CH 6 - DRUG BINDING INTERACTIONS 197
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Chelation and Complexation
The final two binding interactions are chelation and complexation. Chelation is a process that occurs
whenever two distinct electron donating groups, present on the same molecule, bind to a metal ion
and form a ring structure. An example of this is shown below with ethylenediaminetetraacetic acid
(EDTA), a drug that is used for the treatment of lead toxicity, hypercalcemia, and cardiac glycosideinduced arrhythmias. The negative charges on the adjacent carboxylic acid groups can bind to, or
chelate, positively charged metal ions. Shown here is the chelation with lead, but EDTA can also
chelate calcium, iron, mercury, and other metals.
Chelation therapy is also important in the treatment of Wilson’s disease, a genetic disorder
resulting in inappropriate copper transport and the accumulation of copper in the liver, brain, kidneys, and eyes. This accumulation leads to tissue damage and prevents the affected organs from
functioning normally. Penicillamine and trientine (Figure 6-27) can chelate copper, increase its elimination in the urine, and restore copper levels to their normal values. Due to the lack of a sulfhydryl
group, trientine has been shown to produce fewer adverse effects than penicillamine. Please note
that the chelation of trientine and penicillamine with copper occurs when their respective amine
nitrogen atoms are in their unionized form.
FIGURE 6-27.The chelation of copper by penicillamine and trientine.
In addition to treating certain toxicities and elevated levels of specific metal ions, chelation and
complexation are important for the mechanisms of action of a select number of individual drugs
and classes of drug molecules. Most chelates involve oxygen, nitrogen, and/or sulfur atoms that are
present within the functional groups of a drug molecule. Additionally, most chelates form five- or
six-membered rings, although as evidenced with EDTA, larger as well as smaller chelates are capable of forming. In general, four-membered rings occur only if sulfur is involved. Let us look at a few
examples.
Zileuton, shown in Figure 6-28A, is indicated for the treatment of asthma. It acts by inhibiting the enzyme 5-lipoxygenase and thus prevents the formation of leukotrienes, endogenous compounds that are known to contribute to inflammatory responses related to certain disease states. In
the initial step of leukotriene formation, 5-lipoxygenase catalyzes the addition of a peroxide group
to the C
atom of arachidonic acid. This reaction requires both oxygen and an iron atom that is
5
198 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
normally present within the enzyme’s active site. Zileuton inhibits 5-lipoxygenase due in part to
its ability to chelate iron. A second example is seen in the mechanism of action of the tetracycline
class of antibiotics. These drugs inhibit bacterial protein synthesis by binding to the bacterial 30S
ribosome and preventing the binding of transfer RNA (tRNA). Resident within the 30S binding site
is a magnesium ion that is important for tRNA binding. As shown in Figure 6-28B, tetracyclines, by
virtue of their β-dicarbonyl group, can form a chelate with this magnesium ion. This interaction is
important for their ability to bind to the 30S ribosome and produce their antibacterial effect.
FIGURE 6-28.Additional examples of chelation.
Chelation is also responsible for some specific drug interactions. A good example of this is seen
with the tetracyclines. The β-dicarbonyl group discussed above can also form chelates with calcium,
magnesium, aluminum, and iron in the GI tract. These chelates have very poor water solubility;
hence, their formation significantly decreases the absorption of tetracyclines. Antacids, dairy products, vitamins, and other preparations containing these metal ions can therefore cause drug interactions if taken concurrently with a tetracycline. As such, preparations containing these metals need
to be taken at least 1 to 2 hours before or after the administration of a tetracycline. This same drug
interaction also occurs with the fluoroquinolone (e.g., ciprofloxacin) class of antibiotics. As shown
below, the quinolone oxygen atom and the carboxylic acid of ciprofloxacin can form a chelate with
a metal ion. Similar to tetracyclines, products containing aluminum, magnesium, calcium, iron, or
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other trace metals need to be administered at least 1 to 2 hours before or after the administration
of a fluoroquinolone.
A related type of bond occurs whenever a metal ion interacts with a single atom. In this case,
the metal ion does not form a ring, and the process is known as metal complexation. Similar to
chelation, this type of interaction is important in the binding of drug molecules to specific enzymes.
Angiotensin-converting enzyme (ACE) is a zinc protease that catalyzes the conversion of angiotensin
I to angiotensin II. Angiotensin II, when bound to its biological target, has a number of effects on the
cardiovascular and renal systems, including an increase in blood pressure, a release of aldosterone,
and an increase in sodium reabsorption. Inhibitors of ACE are used to treat hypertension, heart failure, and other cardiovascular disorders. As shown in Figure 6-29, a key binding interaction between
these drugs and ACE involves the complexation of either a sulfhydryl group or an ionized carboxylic
acid with the zinc atom. The term complexation is used here because a metal ion is involved; however, the interaction between the zinc ion and sulfhydryl group of captopril could also be designated
as an ion-dipole bond whereas the interaction involving the carboxylic acid of ramiprilat could also
be designated as an ionic bond.
FIGURE 6-29.The complexation of the ACE inhibitors captopril and ramiprilat with a zinc
atom present in the enzyme active site.
200 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
Summary of Key Concepts for Noncovalent Drug Binding
Interactions
• The overall binding strength of a drug to its biological target is a summation of all
individual noncovalent interactions.
• The formation of each noncovalent bond is inversely proportional to the distance
between the functional groups present on the drug molecule and on the biological target.
Steric factors that would prevent the required distance would hinder or prevent
drug binding.
• The ionization state of acidic and basic functional groups plays a key role in determin-
ing what types of noncovalent bonds can and cannot be formed.
Prior to evaluating the types of binding interactions that an acidic or basic functional group can form, it is first necessary to determine if the functional group is
primarily ionized or primarily unionized at a pH of 7.4.
• Ionic bonds involve full positive and negative charges, can occur at the longest dis-
tance, and often provide the initial recognition between a drug and its biological target.
• Dipole–dipole interactions between functional groups involve partial charge separa-
tions between atoms due to their varying electronegativity values.
The most common type of dipole–dipole interaction is a hydrogen bond.
When identifying a hydrogen bond, it is important to indicate which functional
group is the donor and which functional group is the acceptor.
• Ion–dipole interactions occur between a functional group with a full charge and a func-
tional group with a partial charge.
When identifying an ion–dipole interaction, it is important to indicate which functional group has the ionic charge and which functional group has the partial charge.
• Hydrocarbon chains and rings do not have measurable dipoles but can form van der
Waals interactions.
These interactions include dipole-induced dipole interactions and induced dipoleinduced dipole interactions, with the latter being more common.
Induced dipole-induced dipole interactions are most likely to occur when the functional groups have minimal steric hindrance, are conformationally flexible, and are
located in nonpolar regions.
A hydrophobic effect is associated with an induced dipole-induced dipole interaction) and is due to the gain of entropy.
• Aromatic rings and ring systems can participate in π−π stacking interactions, cation–π
interactions, and/or charge transfer interactions.
When identifying a cation–π interaction, it is important to indicate which functional group has the π electrons and which functional group has the cation.
When identifying a charge transfer interaction, it is important to indicate which
aromatic system is electron rich and which is electron poor.
• Metal ions can form binding interactions with functional groups on drug molecules
through the processes of chelation and complexation.
CH 6 - DRUG BINDING INTERACTIONS 201
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STRUCTURAL ANALYSIS CHECKPOINT
Checkpoint Drug 1: Venetoclax
1. Shown above is the structure of venetoclax. Four of its functional groups have been boxed.
For each functional group, complete the following tasks:
A. Identify all possible drug binding interactions. Assume that these drug interactions are
occurring at a physiologic pH of 7.4.
B. Identify one amino acid that could participate in each of the drug binding interactions
you listed in part 1A. Try to identify a wide variety of amino acids rather than using the
same one multiple times.
2. If venetoclax interacted with DNA, which of drug interactions you listed in part 1A would
be possible?
3. Based on the functional groups present within the structure of venetoclax, is it possible for
this drug to form covalent bonds with its biological target? Why or why not?
Checkpoint Drug 2: Elamipretide
1. Four of the functional groups within the structure of elamipretide have been boxed.
Complete the following tasks for each of these functional groups and fill in the table
provided.
A.
Identify two possible drug binding interactions with an amino acid side chain (as the
drug molecule is drawn).
B. Identify two possible drug binding interactions with an amino acid side chain (in an
environment in which pH = 7.4).
C. List one unique amino acid that could participate in each of the drug binding interac-
tions you identified (in an environment in which pH = 7.4).
202 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
Interactions
Functional
Group Name
A 1. 1. 1.
B 1. 1. 1.
C 1. 1. 1.
D 1. 1. 1.
Possible
(as Drawn)
2. 2. 2.
2. 2. 2.
2. 2. 2.
2. 2. 2.
Interactions
Possible
(at pH = 7.4)
Amino Acid Whose Side
Chain Can Interact with
the Functional Group at
pH = 7.4
2. Which functional groups (A–D) can participate in the following types of interactions (at pH
= 7.4)? List all correct answers.
A. Cation-π
B. Ionic
C. Chelation
D. van der Waals
E. Ion-dipole (as the dipole)
CH 6 - DRUG BINDING INTERACTIONS 203
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REVIEW QUESTIONS
1. Bambuterol is a β2 receptor agonist that is a long-acting bronchodilator. Evaluate the structure below to determine what type of interactions might be possible between this drug
molecule and its biological target. As a reminder, a review of amino acids can be found in
Chapter 2 and Table 6-4.
Name of
Functional
Group
a
“None” is a possible answer.
Acidic, Basic,
or Neutral
(as Drawn)
Ionized,
Unionized or
not Ionizable
(at pH = 7.4)
Hydrogen
Bond Acceptor,
Donor, Both,
or Neither
(at pH = 7.4)
Amino Acids Whose
Side Chain Can Interact
with the Functional
Group via Hydrogen
Bonding (at pH = 7.4)
a
2. Consider the molecule of atorvastatin drawn below. The para fluoro substituent, the
amide, and the isopropyl groups can participate in different types of interactions with the
amino acids found in the active site of HMG CoA reductase. Modify the diagram below to
show the interactions of these functional groups with the relevant amino acid side chain.
Label each interaction type.
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