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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5323_Библиотеки_им_академика_М_И_Перельмана
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164 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
A. For each of these drug molecules, complete the structure evaluation in the grid on the
next page:
Functional Group Name
Terconazole
Fluconazole
Miconazole
Hydrophilic and/or
Hydrophobic
Contribution to Aqueous
Solubility and/or Absorption
B. Using the information that you obtained in the structure evaluation process on the
previous page, provide a structural rationale for why miconazole and terconazole can
be administered topically. Why is it appropriate to treat a vaginal yeast infection with
a topical agent?
C. Fluconazole is administered orally and is an exceptionally effective treatment for vagi-
nal yeast infections. What kind of characteristics (properties) must a drug have to be
given orally? Provide a structural rationale for why fluconazole can be administered
via an oral route.
12. Each of these drug molecules treats a particular ailment by either managing a symptom
or modulating a biochemical pathway. In either case, the drug has to get to its biological target. Using your knowledge about functional group character, describe how both
of the drugs get to their respective biological targets. Consider the concepts of solubility,
absorption, distribution, and route of administration in your answer [pH (stomach) = 1; pH
(intestine) = 8; pH (plasma) = 7.4].
Biological Targets and Routes of Administration
Loperamide: μ opioid receptors located in the large intestine; oral administration.
Scopolamine: muscarinic acetylcholine receptors (M1) located in the peripheral nervous
systems; transdermal administration.
DRUG BINDING
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6
INTERACTIONS
LEARNING OBJECTIVES
After completing this chapter, students will be able to
• Explain the differences between covalent bonds and noncovalent bonds.
• Identify the major types of covalent bonds and explain both the beneficial and detrimental
effects that these types of bonds can have on the activity of drug molecules.
• Explain why each type of noncovalent bond has a unique distance requirement and bond
energy.
• Analyze a drug molecule and identify the types of bonds that can be formed by each of its
functional groups.
• Identify specific amino acids, nucleotides, and functional groups present on biological
targets that are capable of forming specific types of bonds.
• Explain how specific situations, such as adjacent functional groups or steric hindrance, can
alter the formation of specific types of bonds.
Drug molecules can form numerous types of covalent and noncovalent bonds (Table 6-1) with
specific biological targets. These biological targets can be organized into four general categories
(receptors, enzymes, nucleic acids, and excitable membranes/other biopolymers) and are typically
composed of proteins or nucleic acids. Drug molecules can also form bonds with chemical entities,
including trace metals, and other coadministered drugs, vitamins, and/or herbal products. The number of bonds, as well as the types and strengths of these bonds, depends on the chemical nature
of the functional groups present in the drug molecule as well as the biological target or xenobiotic.
Minor variations in the structure of a drug molecule can tremendously alter the types and strengths
of binding interactions and contribute to the overall potency, efficacy, and duration of the drug.
This chapter reviews the major types of binding interactions that can be formed between a drug
molecule and its biological target(s), the functional groups that are capable of forming these bonds,
the relative strengths and requirements for these bonds, and the functional groups present on the
biological targets that are involved in these interactions.
DOI 10.37573/9781585286959.006
165
166 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
TABLE 6-1.Types of Bonds Available for Drug Molecules
Covalent Bonds
• Alkylation reactions
• Acylation reactions
• Phosphorylation reactions
• Rearrangement reactions
Noncovalent Bonds
• Ionic bonds
• Dipole interactions
• Ion–dipole interactions
• Dipole–dipole interactions
• Hydrogen bonds
• van der Waals interactions
• Debye forces
• London dispersion forces
• Hydrophobic effects
• Additional aromatic interactions
• π−π stacking interactions
• Cation–π interactions
• Charge transfer interactions
• Chelation and complexation
COVALENT BONDS
A covalent bond is the strongest bond that can be made between a drug molecule and its biological target. The overall strength of a covalent bond can vary but is generally in the range of 40 to
150 kcal/mol. As such, most covalent bonds are too strong to be spontaneously cleaved in normal physiologic environments and are generally considered to be irreversible bonds. It is possible
for some covalent bonds to be cleaved by enzymatic or acid/base catalyzed reactions; however,
depending on the specific covalent bond, this is not always possible. In most cases, when a drug
forms a covalent bond with its biological target, the only way to reverse this action is by the normal
metabolic turnover of enzymes and receptors and the cellular replenishment or replacement of irreversibly inactivated enzymes or proteins. Please note that this turnover requires nuclear transcription, cellular translation, and posttranslational modification to produce a new protein or enzyme.
Additionally, it is possible for some covalent bonds between drug molecules and DNA to be reversed
by normal DNA repair enzymes.
Concerns With the Use of Covalent Bonds
Only a small number of drugs act by forming covalent bonds with their biological target. This is
not due to a lack of therapeutic efficacy because covalently bound drugs are as effective and, in
some cases, more effective than noncovalently bound drugs. For example, aspirin, thienopyridine
antithrombotic agents, β-lactam antibiotics, and alkylating agents (Figure 6-1) all act through the
formation of covalent bonds and are very effective for the treatment/prevention of thrombotic
events, bacterial infections, and cancer, respectively. In fact, the ability of aspirin to irreversibly acetylate platelet cyclooxygenase-1 (COX-1) is responsible for the selective, beneficial cardiovascular
effects of low-dose aspirin therapy.
There are several reasons why covalently bound drugs are not used as frequently as noncovalently bound drugs. First, due to the bond strength, the actions of covalently bound drugs cannot be readily reversed. As discussed above, the reversal of effects can occur only through specific
catalytic processes or the formation of new proteins and enzymes. These processes take longer than
the simple dissociation of a noncovalently bound drug from its biological target. As such, the overall duration of action of a covalently bound drug may be too long for a given therapeutic indication. Noncovalently bound drugs generally have durations of actions appropriate for daily dosing
CH 6 - DRUG BINDING INTERACTIONS 167
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FIGURE 6-1.Examples of drugs that form covalent bonds with their target receptor.
regimens; however, it should be noted that in some cases covalently bound drugs can provide an
optimal duration of action. As an example, rapid tubular secretion very quickly eliminates β-lactam
antibiotics from the body; however, due to the covalent binding of these drugs, their overall actions
last much longer than their half-lives would suggest. Many β-lactam antibiotics, specifically the
cephalosporins (e.g., cefoxitin in Figure 6-1), can be dosed once or twice daily due to their covalent,
irreversible binding to transpeptidase, a bacterial enzyme that is required in the cross-linking of bacterial cell walls. In conclusion, the duration of action of covalently bound drugs is a valid concern but
does not always prevent their use.
Another concern with covalently bound drugs is their specificity for their biological target.
Although binding specificity is important for all drugs, it is even more crucial with covalently bound
agents because it is highly undesirable for a drug molecule to indiscriminately form covalent bonds
throughout the body. A lack of sufficient specificity and irreversible bonds could lead to prolonged
adverse effects. Based on the severity of these adverse effects, the ability to either reverse them or
limit their duration may be a critical choice in the decision to use a covalently bound drug or not.
Finally, some drugs that form irreversible, covalent bonds may require specific handling and guidelines for their administration. This is true for certain alkylating agents used to treat specific types of
cancer (e.g., chlorambucil in Figure 6-1). These drug molecules are highly reactive and require special preparation and administration guidelines. Whereas all drugs that form covalent bonds possess
some degree of reactivity greater than that of noncovalently bound drugs, it is incorrect to make
a blanket statement that all covalently bound drugs are difficult to administer. Aspirin, β-lactam
antibiotics, and thienopyridine antithrombotic agents (Figure 6-1) can all be safely administered as
oral tablets and capsules without any additional warnings or precautions.
Specific Types of Covalent Bonds
The four most common mechanisms by which drug molecules can form covalent bonds are as
follows:
y alkylation
y acylation
168 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
y phosphorylation
y rearrangement reactions that reveal a highly reactive intermediate
The following discussions examine these mechanisms and provide specific examples of drugs
that use these mechanisms to produce their therapeutic effects.
Alkylation
Alkylation occurs when a nucleophilic atom or functional group present in receptors, DNA, or other
biological targets attacks a highly electrophilic atom or functional group present in the drug molecule. As discussed in Chapter 2, nucleophiles are nucleus loving and generally contain either a
negative charge or a lone pair of electrons, whereas electrophiles are electron loving and generally
contain a positive charge, a conjugated double bond system, or a functional group that can be easily
displaced and released. Chlorambucil is used to treat Hodgkin’s disease, non-Hodgkin’s lymphoma,
and a variety of other neoplastic disorders. It is chemically classified as a β-chloroethylamine but
is often referred to as a nitrogen mustard. Chlorambucil alkylates DNA via the mechanism shown
in Figure 6-2. The initial step involves the nucleophilic attack of the lone pair of electrons present
on the tertiary amine on either one of the β-carbon atoms. This attack causes the chloro group to
leave and results in a highly reactive electrophile known as an aziridinium ion. In the second step, a
nucleophile from a biological target attacks the aziridinium ion, resulting in an alkylated macromolecule. The N
the aziridium ion is highly reactive and can also react with other biological targets. This reaction can
then repeat using the other chloro group. The end result is a cross-link in DNA that ultimately leads
to the anticancer effect.
atom of a guanine residue present on DNA usually serves as the nucleophile; however,
7
FIGURE 6-2.The mechanism of alkylation of a macromolecule by chlorambucil.
(Nuc-Macromolecule = nucleophile present on a biological macromolecule; e.g., DNA,
protein, enzyme.)
Acylation
Acylation occurs when a nucleophilic atom or functional group present on a protein, enzyme, or
other biological target attacks an ester, lactone, amide, lactam, or carbamate functional group present on a drug molecule. The resulting product contains an acyl group. The general structure of an
CH 6 - DRUG BINDING INTERACTIONS 169
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acyl group is shown below. Depending on the R group, the acyl group may also have a specific name.
For example, if the R group is a methyl group, the acyl group is commonly known as an acetyl group.
Additionally, if the R group is an amine (primary, secondary, or tertiary), the acyl group is commonly
known as a carbamate. The formation of an acetyl group is also known as acetylation, and the formation of a carbamate is also known as carbamylation.
Let us look at three examples of acylation. The β-lactam class of antibiotics exerts their mechanism of action by inhibiting transpeptidase, a bacterial enzyme responsible for cross-linking bacterial
cell walls (Figure 6-3). Because human cells do not have cell walls, this biological target is found
only in bacteria. A serine residue found within transpeptidase is responsible for recognizing D-AlaD-Ala dipeptide sequences on newly synthesized cell wall precursors. The serine initially cleaves
D-Ala-D-Ala bonds and forms an esterified intermediate that is eventually used to cross-link the cell
wall precursors. β-Lactam antibiotics, exemplified by cefoxitin in Figure 6-3, mimic the D-Ala-D-Ala
sequence of cell wall precursors. As a result, transpeptidase binds to β-lactam antibiotics, cleaves
the β-lactam bond, and becomes irreversibly acylated.
FIGURE 6-3.The acylation of transpeptidase by cefoxitin, a a-lactam antibiotic.
170 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
A second example of acylation is seen with aspirin. Aspirin is a nonsteroidal anti-inflammatory
drug (NSAID) and is unique from all other drugs in this class in that it is the only one that acts in a
covalent manner. All other NSAIDS exert their actions via noncovalent interactions. Additionally,
most NSAIDs exert their mechanism of action by nonselectively inhibiting both COX-1 and -2
enzymes whereas aspirin is 170-fold more selective for COX-1. Cyclooxygenase enzymes are involved
in the biosynthesis of prostaglandins. Prostaglandins are endogenous molecules that produce a variety of beneficial therapeutic effects but also play a role in inflammation, pain, and fever. As such,
inhibitors of COX enzymes are useful as anti-inflammatory agents, analgesics, and antipyretics. As
shown in Figure 6-4, once aspirin binds to COX-1, the primary hydroxyl group of this serine can act
as a nucleophile and attack the acetyl group of aspirin. This results in the release of salicylic acid
and the irreversible acetylation of COX-1. The covalent, irreversible nature of this mechanism is the
reason why low-dose aspirin is used as an antithrombotic agent for certain cardiovascular disorders.
Among the various prostaglandins, thromboxane A2 (TXA2) and prostacyclin (PGI2) are responsible
for maintaining an appropriate balance between the aggregation of platelets and the inhibition of
this process. Thromboxane A
is synthesized in the platelets and requires COX-1, and its release
2
enhances platelet aggregation, whereas PGI2 is synthesized in the blood vessels, requires COX-2,
and acts to inhibit platelet aggregation. The key difference here is that platelets, unlike most cells,
do not have a nucleus. Thus, a low dose of aspirin when given once daily has a more profound effect
on platelets than it does on blood vessels. Because the platelets do not have a nucleus, they cannot
synthesize new copies of COX-1 to replace the irreversibly inhibited acylated enzymes. Thus, aspirin’s effect lasts the lifetime of the platelet, normally 7 to 11 days. In contrast, cells that comprise
blood vessels contain a nucleus and can synthesize more copies of COX-2. The overall net effect is a
decrease in platelet activity and an antithrombotic effect.
FIGURE 6-4.The acetylation of COX-1 by aspirin.
Unlike the previous two examples, there are some instances in which the acylation of a biological target is not truly irreversible. Over time, some acylated groups can be hydrolyzed, thus restoring
the original receptor or enzyme function. In these cases, the bond is said to be pseudo-irreversible.
A good example of this is seen with the third example using neostigmine, a carbamate inhibitor of
acetylcholinesterase indicated for treatment of myasthenia gravis. As shown in Figure 6-5, the serine hydroxyl group of acetylcholinesterase is nucleophilic and is responsible for attacking the acetyl
carbonyl of acetylcholine. The resulting acetyl group is rapidly hydrolyzed, and acetylcholinesterase
is regenerated almost immediately. Neostigmine is structurally similar to acetylcholine; however, it
contains a carbamate group instead of the normal acetyl group. Acetylcholinesterase binds neostigmine, and the serine hydroxyl group of the enzyme again acts as a nucleophile and attacks the
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FIGURE 6-5.Acetylcholinesterase: normal mechanism and pseudo-irreversible inhibition
by neostigmine.
carbamate group of neostigmine. The carbamylated enzyme is much more resistant to hydrolysis,
resulting in a pseudo-irreversible bond. Over time, the carbamate is hydrolyzed and acetylcholinesterase is regenerated. For neostigmine, the time needed for enzyme regeneration is long enough for
it to be dosed three or four times daily.
Phosphorylation
This type of covalent bond can be formed with organophosphates. Isofluorophate and other molecules in this chemical class were once used as ophthalmic agents to decrease intraocular pressure
associated with glaucoma. Today, organophosphates are primarily used as insecticides or as military nerve gases and are quite toxic due to the irreversible inhibition of acetylcholinesterase. The
mechanism of action is very similar to the pseudo-irreversible carbamates, with the main difference
being that phosphorylation of the serine hydroxyl group can become truly irreversible. As shown in
Figure 6-6A, the initial phosphorylation produces an intermediate with three phosphoester bonds.
172 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
Hydrolysis of either of the isopropyl phosphoester bonds creates a negative charge, makes the
remaining phosphoester bonds much less electrophilic, greatly decreases the likelihood that the
bond to the serine hydroxyl group of acetylcholinesterase will be broken, and irreversibly inhibits
the enzyme. This process is known as aging and, as the name implies, it occurs over a period of time.
Prior to the hydrolysis of either of the isopropyl phosphoesters, the administration of pralidoxime
chloride (2-PAM) can reverse the phosphorylation, as shown in Figure 6-6B. Pralidoxime is an antidote for organophosphate poisoning and works by displacing the di-isopropyl phosphate from the
active site of acetylcholinesterase. This reaction occurs because the oxime hydroxyl group of 2-PAM
has a higher affinity for the phosphate than does the serine hydroxyl group of acetylcholinesterase.
Thus, 2-PAM readily displaces di-isopropyl phosphate and regenerates acetylcholinesterase.
FIGURE 6-6.(A) The phosphorylation of acetylcholinesterase by isofluorophate.
(B) Reversal of phosphorylation by 2-PAM.
CH 6 - DRUG BINDING INTERACTIONS 173
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Rearrangement Reactions
A handful of other drugs form covalent bonds with their biological targets as a result of specific
metabolic activation and the rearrangement of existing functional groups to produce a reactive
intermediate. A good example of this can be seen with clopidogrel, a thienopyridine antithrombotic drug (Figure 6-7). Clopidogrel is initially oxidized to 2-oxoclopidogrel. This is followed by a
keto-enol tautomerization and the hydrolytic opening of the thiophene ring to produce the active
metabolite. The thiol group forms a disulfide bond with a specific receptor found on platelets. This
covalent bond prevents adenosine diphosphate (ADP) from binding to the platelet receptor and
inducing platelet aggregation. Clopidogrel and other drugs within this chemical class are useful for
the treatment of a variety of cardiovascular disorders, including acute myocardial infarction and
unstable angina.
FIGURE 6-7.The metabolic conversion of clopidogrel to its active metabolite.
NONCOVALENT BONDS
Most drugs bind to their biological targets through the formation of noncovalent bonds. Compared
with covalent bonds, noncovalent bonds are much weaker, with the bond strengths (or the bond
energies) of individual noncovalent bonds generally ranging from 0.5 to 10 kcal/mol. Although each
individual drug–biological target interaction may appear weak, drugs that bind in a noncovalent
manner form multiple interactions with their biological target. Thus, the overall binding strength is
a summation of all of the individual noncovalent interactions. This binding strength is related to the
overall affinity, or attraction, of a drug molecule to its biological target. In pharmacological terms,
the affinity of a drug molecule for its biological target is often represented as an equilibrium between
the bound versus unbound drug. Dissociation constants are used to compare the relative affinities
of specific drugs to a specific biological target and inherently include the overall binding strengths
of the drugs. As long as appropriate plasma levels are maintained, drugs that bind in a noncovalent
manner are able to bind to their biological targets and provide their desired therapeutic effects.
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