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204 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
3. Evaluate cefprozil and complete the grid to determine which interactions are possible with
the side chain of each of the four amino acids. Be careful to pay attention to the ionization
state of each functional group and amino acid side chain in your evaluation.
Name of
Functional
Group
Acidic,
Basic,
Neutral
(as Drawn)
H-bond
Acceptor,
Donor, Both,
or Neither
(at pH = 7.4)
Interaction
Possible
with Serine
(at pH = 7.4)
Interaction
Possible with
Glutamic
Acid
(at pH = 7.4)
Interaction
Possible
with Lysine
(at pH = 7.4)
Interaction
Possible with
Tryptophan
(at pH = 7.4)
4. Rivaroxaban is a direct Factor Xa inhibitor. It interacts with several amino acids in several
active site pockets. In the S1 pocket, a tyrosine (228) side chain participates in a hydrophobic interaction. In the S4 pocket, a tryptophan (215) side chain participates in a π-π
stacking interaction. The backbone NH of glycine (219) participates in a hydrogen bonding
interaction. Using the figure below, circle and name the functional groups within rivaroxaban that can participate in these interactions, keeping in mind that you should be selecting
functional groups that are in close proximity to the identified amino acids.
CH 6 - DRUG BINDING INTERACTIONS 205
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5. Vorapaxar is a PAR-1 receptor (also known as thrombin receptor) antagonist. Conduct a
functional group evaluation of this molecule to determine which amino acids may be present in the PAR-1 receptor binding site.
Name of One Amino
Acid That Can
Participate in the
Name of
Functional
Group
Acidic, Basic,
or Neutral
Hydrogen
Bond Acceptor,
Donor, Both, or
Neither
Interaction
Possible with the
PAR-1 (Thrombin)
Receptor
Interaction Identified
in the Previous Column
with the Functional
Group (at pH = 7.4)
6. Biktarvy® is considered a complete regimen for the treatment of HIV-1 in adult and pediatric patients. This once daily orally administered triple therapy includes bictegravir, emtricitabine, and tenofovir. Each of the components must be dissolved in the aqueous contents
of the stomach prior to absorption. For each of the drugs drawn below, choose TWO functional groups that could participate in hydrogen bonding interactions with water. For each
interaction, indicate if the functional group is participating as the hydrogen bond donor or
acceptor.
206 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
7. Dopamine is a catecholamine that interacts with the D1 receptor via interactions with three
amino acids that are found in two of the seven transmembrane domains that make up the
receptor. The key amino acids have been identified in the diagram below. Determine which
types of interactions are possible between the following pairs of amino acids and the functional groups found within dopamine:
A. Asp
B. Ser
114
and primary amine
194
and Ser
197
and catechol
8. In the presence of zinc, insulin forms a stable, inactive zinc-insulin hexamer. Within this
hexamer, a histidine residue found within each of the insulin molecules complexes with a
pair of zinc atoms. For the insulin to be biologically active, the hexamer must break up and
each monomer must diffuse away from the zinc atoms. Using the structure below, draw a
diagram that shows how the side chain of histidine complexes with zinc.
CH 6 - DRUG BINDING INTERACTIONS 207
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9. Sacubitril is a neprilysin inhibitor used in the management of heart failure. It interacts with
the enzyme via three pockets (P1, P1′, and P2′). In the P1 pocket, an active site zinc atom is
present; in the P2′ pocket, an active site arginine residue is present.
A. Determine the ionization state of each eligible functional group within sacubitril at
physiologic pH 7.4 as well as with the active site arginine residue.
B. Determine the interactions possible with the functional groups within sacubitril and
the zinc atom and the arginine residue.
C. Circle the functional groups within sacubitril that can participate in ionic interactions
with the zinc atom and the arginine residue.
D. What type of binding interaction do you anticipate occurring in the P1′ pocket? Name
three amino acids that could participate in that interaction with the biphenyl functional group positioned in that pocket.
10. Consider the structural features found in nonoxynol-9 and cannabidiol drawn below.
Provide a brief rationale for why it is likely that these drugs participate in van der Waals or
hydrophobic interactions.
11. In the management of peripheral artery disease, the active form of clopidogrel binds irreversibly to the platelet P2Y12 (ADP) receptor. Describe the advantages and disadvantages
associated with drugs that covalently bind to their biological target.
208 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
12. Each of the three odorant molecules drawn below produces a unique scent upon interaction with the olfactory receptors. Unlike most biological targets for drug action, olfactory
receptors typically have an affinity for a wide variety of odorant molecules and can adopt
unique conformations to enhance the affinity of a given odorant for the receptor. Based
on the structural features found in each molecule, indicate which functional group(s) can
participate in each of the interactions identified.
Sclareol Vanillin Nerolidol
Interaction
Type
van der Waals,
hydrophobic
Hydrogen bond
(acceptor and
donor)
Ion-dipole (as
the dipole)
Functional
Group
Interaction
Type
van der Waals,
hydrophobic
Hydrogen bond
(acceptor)
Hydrogen bond
(donor)
Ion-dipole (as
the dipole)
Functional
Group
Interaction
Type
van der Waals,
hydrophobic
Hydrogen bond
(acceptor and
donor)
Functional
Group
STEREOCHEMISTRY AND
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7
DRUG ACTION
LEARNING OBJECTIVES
After completing this chapter, students will be able to
• Identify chiral and prochiral carbon atoms that are present on drug molecules.
• Explain the similarities and differences between enantiomeric drugs, including the various
ways in which the enantiomers of a drug molecule could affect its pharmacological actions.
• Compare and contrast the following stereochemical designations: (+)/(–), d/l, /, and R/S.
• Explain how R/S designations are assigned and be able to apply this information to a given
chiral center.
• Explain why one enantiomer would have a greater affinity for a given biological target
compared with the other enantiomer.
• Identify diastereomers and geometric isomers and explain how these stereoisomers differ
from enantiomers.
• Explain how conformational isomers differ from configurational isomers.
Draw conformational and configurational isomers of a given drug molecule.
•
• Explain the difference between the active and preferred conformations of a drug molecule
and how this affects the ability of drug molecules to bind to their biological targets.
• Explain how conformational restriction and flexibility can provide therapeutic advantages.
Textbooks, drug prescribing information, online drug information sources, and course lecture notes
often represent drug molecules as flat, two-dimensional objects, when in fact these drug molecules,
as well as the enzymes, receptors, and other biological targets with which they interact, are actually three-dimensional objects. Thus, these overall binding interactions can only occur if there is a
complementary spatial or steric orientation of the required functional groups.
This chapter focuses on two major topics areas: stereoisomers, which are also known as configurational isomers, and conformational isomers. Stereoisomers occur whenever a molecule possesses
a chiral or asymmetric center. Conformational isomers can exist in almost all drug molecules and
are the result of the rotation of single bonds. The following concepts are discussed in this chapter:
the identification and d esignation of chiral centers, enantiomers, diastereomers, geometric isomers,
DOI 10.37573/9781585286959.007
209
210 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
conformational isomers, the influence of stereochemistry on drug action, preferred versus active
conformations, and the advantages that conformational restriction or flexibility can impart on drug
action.
CHIRALITY AND ASYMMETRIC CARBON ATOMS
In a broad sense, the term chiral can be used to describe any object that cannot be superimposed
with its mirror image. For this to occur, the object must lack a plane of symmetry. The simplest
and most commonly seen example of chirality is the human hand. Your right and left hands are
nonsymmetrical and mirror images of one another. Regardless of how much you try, it is impossible
to superimpose them on one another. Interestingly, the term chiral comes from the Greek word for
hand, and chiral molecules have been occasionally referred to as having a “handedness.”
Similar to the human hand, a chiral drug molecule lacks a plane of symmetry and cannot be
superimposed upon its mirror image. The drug molecule must have at least one asymmetric atom
that is attached to four different substituents. An example of this is shown below with metoprolol,
a selective β2-adrenergic antagonist. The carbon atom highlighted with an asterisk is attached to
a hydrogen atom, a hydroxyl group, a methylene adjacent to an amine, and a methylene adjacent
to an ether oxygen. Please note that hydrogen atoms attached to carbon atoms are often not displayed; therefore, if only three bonds are shown, the fourth bond must be to a hydrogen atom. Using
this same concept, you should be able to recognize that the circled methylene carbon of metoprolol
is attached to two hydrogen atoms and is thus symmetric or achiral (i.e., lacks chirality). Please note
that the terms asymmetric atom or center, stereogenic atom or center, and chiral atom or center are
all synonymous.
Carbon atoms are, by far, the most common chiral centers present in drug molecules; however,
nitrogen, phosphorous, and sulfur atoms can also serve as chiral centers. An example of a sulfur
atom serving as a chiral center can be seen below with omeprazole, a proton pump inhibitor that is
used to treat a number of gastrointestinal disorders, including gastric ulcers and gastroesophageal
reflux disease. The sulfur atom is attached to an oxygen atom, a methylene carbon, and a benzimidazole ring. Due to the valence of the sulfur atom, it also has an unpaired set of electrons. Thus, the
spatial orientation of these three bonds plus the pair of nonbonded electrons creates an asymmetric
center. Because sulfur, nitrogen, and phosphorus are the exception rather than the rule, the remainder of the chapter focuses solely on chiral, or asymmetric, carbon atoms.
CH 7 - STEREOCHEMISTRY AND DRUG ACTION 211
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In Chapter 5, the concept of using a metabolic pathway to convert a water- or lipid-soluble
prodrug into its active metabolite was introduced. Metabolic pathways can also transform prochiral
carbon atoms into chiral or asymmetric carbon atoms. The term prochiral applies to a tetrahedral
carbon atom that can be converted to a chiral center by changing only one of its attached groups.
An example of this is seen below with phenytoin, an antiepileptic agent that is used to treat a variety
of types of seizures. Phenytoin lacks an asymmetric carbon atom; however, the highlighted carbon
atom has a prochiral nature. It is attached to a carbonyl carbon atom and a nitrogen atom as well
as two unsubstituted phenyl rings. Normal oxidative metabolism of phenytoin introduces a para
hydroxyl group to one of the unsubstituted phenyl rings and converts the prochiral carbon atom to
an asymmetric carbon atom.
A second example of the prochiral nature of specific symmetrical carbon atoms can be seen
with metoprolol (Figure 7-1). As previously discussed, metoprolol is a chiral molecule and contains an asymmetric carbon atom. It also contains several symmetrical carbon atoms. Two of these
atoms, carbon atoms A and B, can be converted to asymmetric carbon atoms through normal metabolic processes. Carbon atom A is attached to a hydrogen atom, a secondary amine, and two methyl
carbon atoms. Oxidation of one of these methyl groups converts carbon atom A to an asymmetric
FIGURE 7-1.Metabolic conversion of prochiral carbon atoms to asymmetric chiral
centers.
212 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
carbon atom because it is now attached to four different substituents. The same is true of carbon
atom B. This methylene group is initially attached to two hydrogen atoms; however, oxidation at
this carbon atom replaces one of the hydrogen atoms with a hydroxyl group and converts the carbon
atom to an asymmetric center. The key point of all of this is that some drug molecules are initially
nonchiral but can be transformed in vivo to either active or inactive chiral molecules. Additionally,
chiral drugs can undergo metabolism to introduce additional asymmetric centers. Because the steric
orientation of complementary functional groups that are present on a drug molecule and its biological target(s) play an important role in drug binding interactions, the conversion of prochiral centers
to asymmetric carbon atoms can play a large role in the activity and/or toxicity of a drug metabolite.
A key skill to master is the ability to identify asymmetric, or chiral, carbon atoms. In many cases,
such as that seen with metoprolol, the chiral center is attached to four separate functional groups,
making identification relatively easy. Other situations require a more systematic evaluation of similar functional groups to discern if they are identical or different. To this end, let’s evaluate each of
the carbon atoms present in β-methyl--glucose.
y Carbon atom 1 is attached to four different substituents: an oxygen atom involved in a
glycosidic bond with the methyl group (carbon atom 7), an oxygen atom within the ring, a
hydrogen atom, and a carbon atom (carbon atom 2). Please note that even though carbon
atom 1 is attached to two oxygen atoms, the oxygen atoms are not identical. Thus, carbon
atom 1 is a chiral center.
y Carbon atom 2 is attached to four different substituents: a hydrogen atom, a hydroxyl
group, and two nonidentical carbon atoms. To verify that the carbon atoms are nonidentical, please note that when you move clockwise around the ring, you encounter three carbon atoms before the oxygen. When you move counterclockwise, you only encounter one
carbon atom before the oxygen. There are other differences as well; however, you need to
find only one difference to conclude that the carbon atoms are not identical. Thus, carbon
atom 2 is a chiral center.
y Carbon atom 3 is attached to four different substituents: a hydrogen atom, a hydroxyl
group, and two carbon atoms that are not identical. Starting at carbon atom 3, you should
notice that carbon atoms 2 and 4 are identical; however, carbon atoms 1 and 5 are different. Carbon atom 1 is attached to two oxygen atoms whereas carbon atom 5 is attached to
only one oxygen atom. Because moving clockwise around the ring is different than moving
counterclockwise, carbon atom 3 is a chiral center.
y Carbon atom 4 is similar to carbon atom 2. It is attached to a hydrogen atom, a hydroxyl
group, and two carbon atoms located at different distances from the ring oxygen. Therefore,
carbon atom 4 is a chiral center.
y Carbon atom 5 is attached to four different substituents: a hydrogen atom, an oxygen
atom, a hydroxymethyl group, and a carbon atom that is part of the ring. Therefore, carbon
atom 5 is a chiral center.
y Carbon atom 6 is a methylene group and is bonded to two hydrogen atoms. Therefore, it
is not a chiral center.
y Carbon atom 7 is part of a methyl group that contains three hydrogen atoms and is thus
not a chiral center.
In summary, β-methyl--glucose contains five chiral centers.
CH 7 - STEREOCHEMISTRY AND DRUG ACTION 213
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Application Question
Shown below is the structure of lomustine, an alkylating agent used for the treatment of
Hodgkin’s disease.
Question: Does this drug contain a chiral carbon atom?
Answer: No, it does not. Lomustine contains two methylene carbon atoms present in the
chloroethyl chain on the right. As previously discussed, methylene carbon atoms are attached
to two hydrogen atoms and are thus symmetrical and achiral. The cyclohexane ring similarly
has five methylene carbon atoms as well as a carbon atom attached to a urea nitrogen atom.
Despite the wedged bond, this carbon atom is not a chiral center. The cyclohexane ring contains a plane of symmetry. Regardless of whether you move clockwise or counterclockwise
around the ring, the atoms are exactly the same. Thus, this carbon atom is not attached
to four different substituents and is not a chiral center. This example, along with that of
b -methyl--glucose, illustrates a key point. Aliphatic rings with multiple substituents often
have multiple chiral centers whereas monosubstituted aliphatic rings are often achiral. A
systematic analysis of each carbon atom allows for the correct identification of chiral centers.
ENANTIOMERS
Enantiomers, as well as diastereomers and geometric isomers, can be classified as stereoisomers or
configurational isomers. Stereoisomers, or configurational isomers, are compounds that have the
same molecular formula and differ only in the stereochemical arrangement of functional groups
attached to one or more atoms. These types of isomers cannot be interconverted without the breaking and reforming of specific bonds.
Enantiomers, or an enantiomeric pair of compounds, are nonsuperimposable mirror images of
one another. To meet these criteria, enantiomers must contain at least one chiral center as part of
their structure. Let’s look at two examples. As shown in Figure 7-2, warfarin contains a chiral center
and can exist in one of two enantiomeric forms. The R and S designations are discussed later in this
chapter. Please note that these stereoisomers are mirror images. When the S enantiomer of warfarin
is flipped 180°, it cannot be superimposed on the R enantiomer due to the chiral center. The phenyl
ring and the bicyclic coumarin ring can be superimposed but the ketopropyl chain cannot.
In contrast to warfarin, irbesartan, shown in Figure 7-3, does not contain a chiral center.
Although it is possible to draw the mirror image of irbesartan, this does not represent its enantiomer. When irbesartan “B” is flipped 180°, it is completely superimposable with irbesartan “A.”
The key point is that enantiomers must meet both criteria, being mirror images of one another and not
superimposable.
While enantiomers must contain at least one chiral center, there is no upper limit to the number of chiral centers that enantiomers can contain within their structures. To illustrate this, consider
enalaprilat, an angiotensin-converting enzyme inhibitor used to treat hypertension, heart failure,
and other cardiovascular disorders. As shown at the top left of Figure 7-4, enalaprilat contains three
chiral centers. The mirror image of enalaprilat is shown on the right. Similar to what was done in the
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