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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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434 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
Checkpoint Drug 2: Elamipretide
1. Answers provided in the table below.
Functional
Group Name
A Guanidine 1. Hydrogen bonding
B Primary
amine
C Amide 1. Hydrogen bonding
D Phenol 1. Hydrogen bonding
Interactions Possible
(as Drawn)
(acceptor and donor)
2. Ion-dipole (as the dipole) 2. Ion-dipole (as the ion) 2. Ser, Thr, Met, Tyr, Cys,
1. Hydrogen bonding
(acceptor and donor)
2. Ion-dipole (as the dipole) 2. Ion-dipole (as the ion) 2. Ser, Thr, Met, Tyr, Cys,
(acceptor and donor)
2. Ion-dipole (as the dipole) 2. Ion-dipole (as the dipole) 2. Glu, Asp, Lys, Arg
(acceptor and donor)
2. Ion-dipole (as the dipole) 2. Ion-dipole (as the dipole) 2. Glu, Asp, Lys, Arg
Amino Acid Whose Side
Chain Can Interact with
Interactions Possible
(at pH = 7.4)
1. Ionic 1. Glu, Asp
1. Ionic 1. Glu, Asp
1. Hydrogen bonding
(acceptor and donor)
1. Hydrogen bonding
(acceptor and donor)
the Functional Group at
pH = 7.4
Gln, Asn, Trp
Gln, Asn, Trp
1. Ser, Thr, Met, Tyr, Cys,
Gln, Asn, Trp. His
1. Ser, Thr, Met, Tyr, Cys,
Gln, Asn, Trp, His
2. Answers provided in the table below.
Interaction Type Functional Groups
Cation-π A, B, D
Ionic A, B
Chelation A, B
van der Waals/Hydrophobic D
Ion-dipole (as the dipole) C, D
Ion-dipole (as the ion) A, B
H-bonding (donor and acceptor) C, D
APPENDIX - ANSWERS TO CHAPTER QUESTIONS 435
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Review Questions
1. Answers provided in the table below.
Amino Acids Whose
Side Chain Can
Ionized,
Acidic, Basic,
Name of
Functional Group
Carbamate (×2) Neutral Not ionizable Both Ser, Thr, Tyr, Cys, Asn,
Secondary alcohol
(or hydroxyl)
Aromatic
hydrocarbon
Secondary Amine Basic Ionized Neither None
Aliphatic alkane Neutral Not ionizable Neither None
a
“None” is a possible answer.
or Neutral (As
Drawn)
Neutral Not ionizable Both Ser, Thr, Tyr, Cys, Asn,
Neutral Not ionizable Neither None
Unionized or
not Ionizable
(at pH = 7.4)
2. The diagram below is labeled to show the interactions between the isopropyl, para-fluoro
phenyl, and amide functional groups and three active site amino acid side chains within
HMG CoA reductase.
Hydrogen Bond
Acceptor, Donor,
Both, or Neither
(at pH = 7.4)
Interact with the
Functional Group via
Hydrogen Bonding
(at pH = 7.4)
Gln, Trp, His, Met
Gln, Trp, His, Met
a
436 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
3. Possible interactions are provided in the grid below.
H-bond
Acidic,
Name of
Functional
Group
Ertapenem
Amide (mono
substituted)
Amide
(Lactam)
Carboxylic
acid
Phenol
(R-OH)
Thioether Neutral Acceptor
Primary
amine
Alkene Neutral Neither None None None van der Waals;
Basic,
Neutral (as
Drawn)
Neutral Both Hydrogen
Neutral Acceptor
Acidic
pKa = 2.5-5
Acidic
pKa = 9-10
Basic
= 9-11
pK
a
Acceptor,
Donor, Both,
or Neither
(at pH = 7.4)
only
Neither
(ionized)
Both Hydrogen
only
Neither
(ionized)
Interaction
Possible
with Serine
(at pH = 7.4)
bonding;
dipoledipole
Hydrogen
bonding;
dipoledipole
Ion-dipole
Drug = ion
bonding;
dipoledipole
Hydrogen
bonding
Ion-dipole
Drug = Ion
Interaction
Possible with
Glutamic
Acid
(at pH = 7.4)
Ion dipole
Drug =
dipole
Ion-dipole
Drug =
dipole
None Ionic Ion-dipole
Ion-dipole
Drug =
dipole
None Ion-dipole
Ionic None Ion dipole
Interaction
Possible
with Lysine
(at pH =
7.4)
Ion dipole
Drug =
dipole
Ion-dipole
Drug =
dipole
Ion-dipole
Drug =
dipole
FG = dipole
Interaction
Possible with
Tryptophan (at
pH = 7.4)
Hydrogen
bonding;
dipole-dipole
Hydrogen
bonding;
dipole-dipole
Drug = ion
OH: Hydrogen
bonding;
dipole-dipole
R: van der
Waals;
Hydrophobic:
π−π stacking
Hydrogen
bonding; van
der Waals;
hydrophobic
interaction
Drug = ion;
Cation-π
interaction
FG = cation
hydrophobic
interaction
4. The functional groups that interact with the amino acid side chains in the S1 and S4 pockets
as well as with the backbone glycine NH are circled and the interactions labeled.
APPENDIX - ANSWERS TO CHAPTER QUESTIONS 437
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5. Functional group evaluation to predict interactions within PAR-1 receptor binding site.
Interaction
Hydrogen Bond
Name of
Functional Group
Ester Neutral H-bond acceptor H-bonding;
Cycloalkane Neutral Neither van der Waals;
Carbamate Neutral H-bond donor and
Alkene Neutral Neither van der Waals;
Aromatic
heterocycle
(pyridine)
Halogenated
aromatic
hydrocarbons
Acidic, Basic, or
Neutral
Basic H-bond acceptor Ion-dipole (as
Neutral H-bond acceptor H-bonding Ser, Thr, Tyr, Cys,
Acceptor, Donor,
Both, or Neither
acceptor
Possible with the
PAR-1 (Thrombin)
Receptor
ion-dipole (as
the dipole);
dipole-dipole
hydrophobic
Ion-dipole;
dipole-dipole;
H-bonding
hydrophobic
the dipole);
dipole-dipole;
H-bonding
Name of One
Amino Acid That
Can Participate
in the Interaction
Identified in
the Previous
Column with the
Functional Group
(at pH = 7.4)
Ser, Thr, Tyr, Cys,
Gln, Asn, Trp, His
Val, Leu, Ile, Met,
Phe, Tyr, Trp
Lys, Arg (ion); Ser,
Thr, Tyr, Cys, Gln,
Asn, Trp; His,
Met (dipole and
H-bonding)
Val, Leu, Ile, Met
Lys, Arg (ion); Ser,
Thr, Tyr, Cys,
Gln, Asn, Trp,
His (dipole and
H-bonding)
Gln, Asn, Trp, His
438 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
6. Functional groups and their hydrogen bonding properties are provided below.
Bictegravir Emtricitabine Tenofovir
Amide (H-bond acceptor and
donor)
Lactam (H-bond acceptor) Urea (H-bond acceptor) Phosphamide (H-bond
Ketone (H-bond acceptor) Primary alcohol (H-bond
Halogenated aromatic
hydrocarbon (H-bond acceptor)
Ether (H-bond acceptor) Thiourea (H-bond acceptor) Primary amine (H-bond
Tertiary amine (H-bond acceptor) Primary amine (H-bond
Ether (H-bond acceptor) Ester (H-bond acceptor)
acceptor and donor)
acceptor and donor)
Fluoro (H-bond acceptor) Ether (H-bond acceptor)
acceptor and donor)
Aromatic heterocycle
(H-bond acceptor)
acceptor and donor)
7. Part A: An ionic interaction occurs between the ionized carboxylic acid found in the side
chain of aspartic acid and the ionized primary amine found in the structure of dopamine.
Part B: The serine hydroxyl group is a neutral functional group and is not ionizable in any
physiologic environment. The catechol is acidic in character and at physiologic pH the
pH < pKa and the catechol is unionized. Both of these functional groups are able to participate in hydrogen bonding or dipole–dipole interactions.
8. The positively charged zinc atom complexes with the lone pair of electrons on the imidazole ring. Although the zinc atom can also complex with an amide carbonyl found on the
peptide backbone of insulin, it is much more likely to complex with the histidine side chain
because this side chain is less sterically hindered and thus more available.
9. Part A: Ionization states are shown below.
APPENDIX - ANSWERS TO CHAPTER QUESTIONS 439
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Part B: In the P1 pocket, the zinc atom and the ionized carboxylic acid can participate in an
ionic interaction. In the P21 pocket, the ionized arginine residue can participate in an ionic
interaction with the ionized carboxylic acid.
Part C: Functional groups that can participate in ionic interactions are circled below.
Part D: In the P11, pocket there can be van der Waals, hydrophobic, or π-π stacking interac-
tions with the biphenyl functional group. The three amino acids most likely to participate
in these interactions are Phe, Tyr, and Trp.
10. Both nonoxonyl-9 and cannabidiol contain unbranched long aliphatic and/or alicyclic
alkanes as well as aromatic rings. These functional groups can participate in hydrophobic
interactions and van der Waals interactions.
11. Drug molecules that covalently bind to their biological targets can demonstrate enhanced
selectivity for their targets and a prolonged duration of action. Let’s look at each of these
properties individually. The enhancement in selectivity is primarily achieved via the use of
prodrugs that are converted to reactive intermediates (active drug) in close proximity to
their biological targets. Proximity of the reactive intermediate and the biological target
is important to maximize so as to avoid unnecessary misadventures between the reactive
intermediate and other proteins present. In fact, it should be noted that those drugs that
bind covalently that are not prodrugs, and therefore do not require in vivo bioactivation,
are generally no more selective than analogous drugs that interact via noncovalent means.
Although drugs that form a covalent bond with their biological target do have a longer
duration of action than drug molecules that participate in noncovalent interactions, it is
important to be cautious when championing this property. It should be no surprise that the
effects of covalently bound drugs are not as readily reversed as those associated with drugs
that participate in noncovalent interactions. As a result, there is a possibility that the overall duration of drug action may be too long for the desired therapeutic effect (representing
a potential disadvantage).
As you might expect, the possibility for a drug misadventure, as mentioned previously, rep-
resents the major disadvantage associated with drugs that form covalent bonds with their
biological targets. Because the active form of the drug is highly reactive, the potential for
the drug to react with a nearby protein can be significant. As a result, special preparation
and administration guidelines may need to be in place to ensure that drug activation occurs
in close proximity to the desired biological target.
440 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
12. Answers provided in the table below.
Sclareol Vanillin Nerolidol
Interaction
Type
Hydrophobic Cycloalkane,
Hydrogen bond
(acceptor and
donor)
Ion-dipole (as
the dipole)
Functional
Group
aliphatic
alkane,
alkene
Tertiary alcohol
(or hydroxyl)
Tertiary alcohol
(or hydroxyl)
Interaction
Type
van der Waals,
hydrophobic
Hydrogen bond
(acceptor)
Hydrogen bond
(donor)
Ion-dipole (as
the dipole)
Functional
Group
Phenol
(specifically
the aromatic
ring)
Phenol, ether,
aldehyde
Phenol
Phenol, ether,
aldehyde
Interaction
Type
van der Waals,
hydrophobic
Hydrogen bond
(acceptor and
donor)
Functional
Group
Aliphatic
alkanes and
alkenes
Tertiary alcohol
(or hydroxyl)
CHAPTER 7
Structural Analysis Checkpoint
Checkpoint Drug 1: Venetoclax
1. The structure of venetoclax does not contain any chiral centers; however, there are
14 potential prochiral centers. These have been identified below. With the exception of
prochiral center 2, the metabolic addition of a functional group to any of these carbon
atoms would result in a chiral center. For prochiral center 2, the addition of a functional
group to either of the adjacent methyl groups would create a chiral center. At this point, we
are only looking at potential prochiral centers. In Chapter 8, after we have discussed all of
the metabolic pathways, we revisit this question to see which of these potential prochiral
centers can actually be converted to a chiral center.
2. Part A: No. Drug molecules need to have at least one chiral center to have enantiomers.
The structure of venetoclax does not contain any chiral centers, so it is not possible for it
to have enantiomers.
Part B: No. Drug molecules need to have at least two chiral centers to have diastereomers.
The structure of venetoclax does not contain any chiral centers, so it is not possible for it
to have diastereomers.
APPENDIX - ANSWERS TO CHAPTER QUESTIONS 441
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Part C: No. Geometric isomers are a specialized type of diastereomers that occur due to the
presence of an alicyclic ring or a double bond. The structure of venetoclax does contain two
alicyclic rings; however, as mentioned above, neither of these contains a chiral center. The
cyclohexene ring that is attached to the para chlorophenyl ring does contain a double bond;
however, due to the geometry and rigidity of a six-membered ring, it is not able to have cis
and trans isomers. To have geometric isomers, the double bond needs to be in an aliphatic
chain and not a ring.
Part D: Yes. Conformational isomers result from the rotation of single bonds with a drug
molecule. Because the structure of venetoclax contains numerous single bonds that can
undergo free rotation, it is possible for venetoclax to have multiple conformational isomers.
3. Shown below are three conformational isomers of venetoclax. Although all of these conformational isomers are possible, conformational isomer 2 requires rotation of a bond involved
in the resonance stabilization of the sulfonamide and may be less likely than the other two.
4. Cyclohexane and other six-membered, nonaromatic, heterocyclic ring systems (i.e., a piperazine ring) can adopt either a chair or boat conformation. Of these two options, chair
conformations are preferred due to lower steric hindrance (or repulsion) and the presence
of staggered bonds (as compared with eclipsed bonds seen in boat formations). Similar
442 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
to chair-chair inversion seen with cyclohexane, the ability of nitrogen atoms to undergo
inversion of their lone-pair of electrons allows for the minimization of steric hindrance
(or repulsion) and the maximization of attractive forces. In the case of venetoclax, the
nitrogen atoms in the piperazine ring are attached to aromatic and alicyclic rings. For steric
reasons, these groups should be oriented such that they both occupy equatorial positions
as shown below.
5. The pyrrolopyridine ring can assume a variety of conformational orientations relative to its
adjacent aromatic ring and the meta piperazine ring and the ortho side chain attached to
this ring. The pyrrolopyridine ring can rotate about two bonds indicated in the structure
below. Due to the rigidity and distance of the piperazine ring, it would not be expected
to influence the conformation of the pyrrolopyridine ring. Rotation about bond A would
allow the pyrrolopyridine ring to lie parallel to the adjacent aromatic ring, perpendicular to
the adjacent aromatic ring, and any intermediate orientation. Minimal steric factors affect
this rotation. Rotation about bond B would allow similar orientations; however, rotations
approaching 135° to 180° would cause increasingly significant steric interactions with
the ortho side chain and would not be favored. In terms of bond B, the orientation shown
below of the pyrrolopyridine with respect to the ortho side chain provides the least steric
hindrance.
APPENDIX - ANSWERS TO CHAPTER QUESTIONS 443
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Checkpoint Drug 2: Elamipretide
1. There are four chiral carbons present in elamipretide.
2. For the arginine component of elamipretide, there are three additional prochiral carbons.
For the tyrosine derivative component of elamipretide, there is one additional prochiral
carbon.
For the lysine component of elamipretide, there are four additional prochiral carbons.
For the phenylalanine component of elamipretide, there is one additional prochiral carbon.
3. Part A: Enantiomers must contain at least one chiral carbon. Elamipretide contains four
chiral carbons. To produce an enantiomer of elamipretide (S,S,R,S = configuration as drawn),
all of the chiral carbons would need to be in their opposite configuration (R,R,S,R).
Part B: For a molecule to have diastereomers, it must contain at least two chiral carbons.
Elamipretide contains four chiral carbons. To produce a diastereomer of elamipretide
(S,S,R,S = configuration as drawn), at least one of the chiral carbons must be in its opposite
configuration (R,S,R,S). There are many, many diastereomers possible for elamipretide!
4. Geometric isomers are not possible for elamipretide because it does not contain a double
bond or alicyclic ring system.
5. Because elamipretide contains numerous rotatable single bonds, not only at the ends of
the molecule but in the middle of the molecule, it is considered conformationally flexible.
In addition, it does not contain any double bonds or rigid ring systems.
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