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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5319_Библиотеки_им_академика_М_И_Перельмана.pdf
. • Structure-Based Design of Nonpeptidic HIV Protease Inhibitors
. Fig. 24.15 To date, nine new compounds for AIDS therapy have
been introduced to the market, whereby nelnavir 24.24 has been
withdrawn from the market in Europe. Compounds 24.19–24.26 are
Anew lead structure 24.34 (Ki = 1.1 μm, . Fig.24.19)
was found in ascreening campaign at Parke–Davis. The
spatial structure with the protease was determined with
the homologous inhibitor 24.38 (. Fig.24.18). It was
shown that this structure, analogous to 24.31, displaces
the water molecule in the active site and forms H-bonds
to the catalytic aspartate residues as well as to the NH
groups of Ile50 and Ile50′. The X-ray structure was used
to design derivatives with improved binding properties,
peptide-like inhibitors, and tipranavir 24.27 alone has acompletely
nonpeptidic structure
such as 24.36. Modeling studies led to the idea of introducing an acidic group into the S3 pocket to form asalt
bridge with Arg8. The corresponding compound with an
OCH2COOH group in the para-position of the 6-phenyl
ring was synthesized and resulted in asignicant increase
in binding afnity. The inhibitor 24.37 (Ki = 51 nM) is
achiral, has alow molecular weight, and can be prepared
in three steps. The hydroxypyrone scaffold ultimately
proved successful for inhibitor development. In 2005,
24
Chapter • Aspartic Protease Inhibitors
. Fig. 24.16 The pattern of the hydrogen
bonds between HIV protease and the peptide
inhibitors in the vicinity of the catalytic
aspartic acids (left). Awater molecule is found
in the binding pocket that forms two H-bonds
to the inhibitor and to the protein. The
hydroxyl group of the inhibitor displaces the
water molecule that is involved in the catalytic
process (cf. . Fig.24.1). By starting with this
binding mode, the spatial pharmacophore of
apotential inhibitor was dened (right). The
search in databases of crystal structures of
low molecular weight compounds was started
with this pattern. It produced the substituted
phenol 24.28 as ahit. From there, six- and seven-membered cyclic ketones and acyclic urea
24.29 were developed. These derivatives could
displace the structurally conserved water molecules from the binding pocket of the protease
with their carbonyl groups
Boehringer Ingelheim launched tipranavir 24.27, the
rst nonpeptidic HIV protease inhibitor. This compound
binds to the catalytic dyad with its hydroxyl function. The
carbonyl oxygen of the pyrone replaces the structural water. Side chain optimization, however, resulted in amuch
more complex structure than that shown in 24.34.
24.5 The Development of Resistance
Against HIV Protease Inhibitors
The rst HIV protease inhibitor was developed and
brought to market in less than 8years. In the following
10years, nine drugs were introduced as marketed products (. Fig.24.15). Compounds from completely different structural classes have been successfully developed to
block the HIV protease. An arsenal of orally available,
small-molecule inhibitors is now available for therapy.
In addition, drug molecules have also been developed
and marketed for another important viral enzyme, the
reverse transcriptase (Sect.32.5). In addition to substrate
analogous inhibitors such as zidovudine (AZT 24.39) and
didanosine (DDI 24.40), allosteric inhibitors (such as nevirapine 24.21) are available (. Fig.24.20). HIV integrase
is another enzyme that has been identied as atarget for
combating the HIV virus. This enzyme integrates viral
DNA transcribed by reverse transcriptase into the host
cell genome. Raltegravir 24.42 became the rst integrase
inhibitor to be approved in late 2007. Other drugs targeting this enzyme followed, including elvitegravir, dolutegravir, bictegravir, or cabotegravir. Common to these drug
molecules is ahydrophobic benzyl group that occupies
ahydrophobic pocket near the active site. They share
achelating triad that binds tightly to two Mg2+ ions, anchoring the inhibitor to the protein surface. Other drugs
include enfuvirtide and maraviroc, which inhibit fusion as
the virus enters infected cells (Sect.31.5). A recent innovation with a novel mechanism of action are HIV capsid
inhibitors. They interfere with the viral capsid, a protein
shell that protects the genetic material and enzymes of
the virus needed for replication after the virus has fused
with the infected host cell. In 2022, lenacapavir became
the rst HIV capsid inhibitor to be approved.
The virus has rapidly developed resistance to reverse
transcriptase inhibitors. Like other RNA viruses, HIV
replication is error-prone. The viral reverse transcriptase
makes an error approximately every 10,000 bases. In this
way, the virus generates large genetic diversity, which leads
. • The Development of Resistance Against HIV Protease Inhibitors
. Fig. 24.17 The newly discovered lead structure of the
cyclic urea 24.29 was optimized stepwise via the derivatives
24.30 and 24.31 to DMP-323 24.32 and DMP-412 24.33 at
Dupont–Merck
. Fig. 24.18 The superimposi-
tion of the crystal structures of
the complexes of HIV protease
with the urea-containing inhibitor
24.31 (gray) and the coumarin
derivative 24.38 (light green).
(7 https://sn.pub/LPXIyG)
directly to resistance. With approximately 108–109 replication cycles per day, 105 point mutations occur in the viral
protein population of an infected patient. It is, therefore,
not surprising that the introduction of HIV protease inhibitors has induced ahigh level of resistance. Various mutations in the binding pocket further away from the active
site also lead to asevere reduction in the binding afnity
of HIV protease inhibitors. The positions where mutations
have been observed are shown in . Fig.24.21. Taking all
the observed exchanges together, half of all positions in
the protease are now affected. However, similar amino acid
exchanges near the catalytic center are observed again and
again. This is certainly due to the fact that the peptide-like
inhibitors 24.19–24.26 all adopt arather similar binding
mode in the protease (see . Fig.24.25).
Therefore, combination therapy is used to treat AIDS.
The simultaneous administration of several inhibitors
should lead to better suppression of viral replication.
24
Chapter • Aspartic Protease Inhibitors
. Fig. 24.19 Optimization of the coumarin-like HIV
protease inhibitor 24.34, which was discovered by mass
screening at Parke–Davis. The extension of the thioether
side chain to 24.35 and 24.36 as well as the introduction
of acarboxyl group led to 24.37. Ahydrogenated hydroxypyrone building block could be incorporated in tipranavir
24.27 at Boehringer Ingelheim. The compound represents
the rst nonpeptide HIV protease inhibitor for therapy
This signicantly slows down and hinders the formation
of resistance. The best results are achieved by combining
antiviral drugs with different modes of action, such as
anucleoside and anonnucleoside reverse transcriptase inhibitor with aprotease inhibitor. Such therapies are part of
the so-called HAART (highly active antiretroviral therapy)
strategy, which has found application in the clinical setting.
24.6 A Basic Nitrogen as aPartner for the
Aspartic Acids of the Catalytic Dyad
As mentioned above, Roche discovered apiperidine derivative 24.13 (. Fig.24.10) in acomprehensive screening
campaign as arenin inhibitor with micromolar activity. It
was further optimized to asubnanomolar hit. Its piperidine nitrogen atom binds at the pivotal point between the
two aspartic acids (. Fig.24.10). As aresult of this work,
secondary amines have now been intensively investigated
as binding partners for the aspartic acids. Awhole series
of building blocks have been described (. Fig. 24.22)
and tested for their inhibitory potency on various aspartic proteases. In arational design approach, ave-membered pyrrolidine ring (24.43) was designed instead of
asix-membered piperidine. Such aring can be placed with
its nitrogen atom between the two aspartic acid residues.
At the same time, the specicity pockets can be reached
. Fig. 24.20 By using HAART therapy, which is acombination of
aprotease inhibitor (. Fig. 24.15), a reverse transcriptase inhibitor
such as 24.39–24.41, or an integrase inhibitor such as 24.42, the hope
is to break through the increasingly observed resistance to the drugs
in AIDS therapy
0
2
0
1
0
1
0
2
0
1
0
2
. • A Basic Nitrogen as aPartner for the Aspartic Acids of the Catalytic Dyad
the S
the bulky dimethylphenoxy group of the molecule appeared to protrude beyond the
with the loop of the ap. Despite asingle-digit micromolar afnity (Ki = 1.5 μM), the inhibitor seemed “uncomfortable” in the pocket. It seemed to break almost all the
“golden” rules of drug design (Sect.4.11). Is the awkward
dimethylphenoxy group responsible for the binding mode?
To test this, athree-armed inhibitor 24.46 (. Fig.24.23)
was synthesized. Surprisingly, the crystal structure of
this inhibitor 24.46 (Ki = 52 μM) shows the same binding
mode: the structural water is displaced and the loop region
. Fig. 24.21 Mutations in the amino acids in HIV protease lead to
resistance to the inhibitors. The course of the polymer chain is coded
in green or red. Red represents residues that, with high probability,
have mutated, and green areas show little exchange. Many mutations
are found in the vicinity of the active site, but some are fairly far away
from the substrate-binding pocket
takes on adistorted shape, although there is obviously no
large group left to interfere with the region (. Fig.24.24,
upper right). The occupancy of the specicity pockets with
this inhibitor seems to be far from optimal.
Next, an attempt was made to bring the substituents on either side of the central pyrrolidine ring closer
together. Andreas Blum eliminated the two methylene
linkers to use 3,4-diaminopyrrolidine 24.44 as the central
symmetrically with its side chains on the prime and unprime sides. As with the substrate-like inhibitors 24.19–
24.26 (. Fig.24.15), hydrogen bond acceptor groups were
included in the design on both sides of the heterocycle.
As mentioned, in the special case of the HIV protease,
aconserved water molecule (so-called structural water) is
found in apivotal position to mediate the interaction to
the ap region. In other aspartic proteases, direct contact
with the ap region is achieved. The pyrrolidine ring was,
therefore, extended by aminomethylene groups on both
sides and amide and sulfonamide groups were introduced
as acceptor functions. At the same time, the amide nitrogen atoms served as branching points to reach the four
subpockets of the protease with attached groups.
In asmall series of compounds, Edgar Specker at the
University of Marburg developed micro- to submicromolar lead structures for HIV protease and cathepsinD.
Using the racemate of 24.45, Jark Böttcher determined
the crystal structure with HIV protease. It contained abig
surprise (. Figs.24.23 and24.24, upper left). The nitrogen
in the pyrrolidine ring of the (R,R)-enantiomer is, as dened, at the pivotal point between the two aspartic acids.
It occupies the same position as the hydroxyl groups in the
transition state analogue inhibitors. However, contrary to
the original concept, the inhibitor displaces the structural
water from the binding pocket! The oxygen of the sulfone
group forms adirect hydrogen bond to the NH group of
Ile50 in the ap. The carbonyl group of the amide bond
on the opposite side is not involved in any interaction with
the ap region. On the other hand, the loop of the ap
adopts adistorted geometry in that the NH function of
Ile50′ results in ahydrogen bond contact with the turn of
the other monomer unit. Such ageometry had never been
seen before. On closer analysis, it appeared that the inhibitor did not optimally ll the S2 to
subpockets of the
protease. Compared to amprenavir 24.23 (. Fig.24.15),
scaffold (. Fig.24.22). This scaffold was symmetrically
decorated on both sides with substituted sulfonamides.
First, benzenesulfonic acid derivatives were optimized
with respect to the substitution at the tertiary nitrogen
atom (24.47–24.58; . Table24.7). In addition to the in-
hibitory effects on the wild-type enzyme, arapidly induced
resistant mutant variant carrying avaline instead of an
isoleucine at position84 was also studied. The enlarged
pocket in the resistant mutant shows reduced binding afnity with many inhibitors due to the reduced hydrophobic contact surface. It was also shown that the wild-type
enzyme does not tolerate branched groups (24.47–24.50)
as well as the mutants (. Table24.7). The benzyl group
proved to be the best compromise for good inhibition of
both isoforms. The crystal structure of derivative 24.47
was determined (. Fig.24.24, lower left). The pyrrolidine
nitrogen atom occupies the desired position between the
two aspartic acids. The structural water is again displaced
from the pocket and one of the two sulfonamide groups
forms ahydrogen bond with the Ile50 NH group in the
ap region. The inhibitor sits largely symmetrically in the
binding pocket. The benzyl groups on the amino group
are located in the S1 and
group occupies the S2 and
be much better lled with this inhibitor than with 24.45 or
24.46. Nevertheless, it was obvious that the substituents
in S1 and
optimization. An additional bromine or iodine substituent increases the afnity about sixfold compared to the
wild type. The inhibition of the mutant is improved by
afactor of2. There even seemed to be enough room for
larger groups in the S2 and
group or achlorine atom in the ortho-position increases
the afnity by afactor of2. This effect was not as pronounced with the mutant. Furthermore, at the end of this
pocket are the acidic amino acids Asp29 and Asp30,
pocket remains virtually unoccupied. In addition,
2
pocket and interfered
pockets. The benzenesulfonyl
pockets. The pockets seem to
in the para-position should be enlarged for
pockets. Indeed, amethyl
24
Chapter • Aspartic Protease Inhibitors
. Fig. 24.22 Secondary amines are promising binding partners for
the aspartic acids of the catalytic dyad of aspartic proteases. In arational design approach, the nitrogen atom of the ve-membered pyrrolidine ring 24.43 was placed between the two aspartic acids. At the same
. Fig. 24.23 Schematic representa-
tion of the different binding modes
of the four inhibitors that are shown
in . Fig.24.24. The three pyrrolidine
derivatives 24.45, 24.46, and 24.47
differ in their connecting geometry at
the ring and the number of substituents. The central heterocycle was
opened in 24.59. Interestingly, the
conserved structural water returns to
the structure with this ligand
time, the scaffold and its side chains symmetrically reach the specicity
pockets on the primed and unprimed side of the protease. The incorporated acceptor function should form H-bonds to the structurally
conserved water molecule in the ap region of HIV protease
ab
cd
0
1
0
1
0
2
0
1
0
2
0
1
. • A Basic Nitrogen as aPartner for the Aspartic Acids of the Catalytic Dyad
. Fig. 24.24 Crystal structures of the inhibitors from . Fig.24.23 in
HIV protease. aCompound 24.45 leaves the S2 pocket virtually unoc-
cupied. Its voluminous o,o′-dimethylphenoxy substituent only incompletely lls the
ap region. The structural water is displaced from the binding pocket.
bCompound 24.46 only partially lls the S2 and
is also displaced from this structure and the loop takes on adistorted geometry even though no unfavorable contacts are recognizable.
cCompound 24.47 binds almost C2 symmetrically and places its ben-
zenesulfonyl groups in S2 and
and
. Here too, the structural water is displaced from the complex.
d Compound 24.59 orients its p-aminobenzenesulfonyl group in S2
which interact with the ligand. This interaction is possible
pocket and seems to push against the loop in the
pockets. Water
. The N-benzyl groups are found in S1
by introducing an amino or carboxamide group in the
para-position. The binding potency to the enzyme is then
increased by afactor of about10. Further optimization
led to derivative 24.58 with aCF3 group on the P1 benzyl group and an amide group on the P2 substituent. It
inhibits the wild-type enzyme with Ki = 61 nM and the
mutant with 14 nM. The binding mode of these new inhibitors, based on a3,4-diaminopyrrolidine 24.44, differs
from that of all other inhibitors currently on the market.
and
. The N-benzyl substituents occupy S1 and
form H-bonds to the structural water, which has returned in this structure. The inhibitor seems to ll the binding pocket perfectly, but it
does not achieve better binding afnity than the other derivatives despite the additional NH2 functions that form H-bonds to the protein.
(7 https://sn.pub/yyNuRq)
. Both SO2 groups
Such adifference may provide apromising perspective for
resistance breaking (. Fig.24.25).
In one of the nal steps, the central heterocycle was
“cut open” and replaced with open-chain secondary
amines (. Fig.24.23). Two- and three-membered aliphatic chains were introduced as spacers between the
central amine nitrogen atom and the two SO2 groups
designed to bind to the ap region. Inhibition constants were measured for several aspartic proteases and
showed single to double digit micromolar inhibition. The
crystal structure of compound 24.59 was determined
CH
3
Cl
Br
I
F
2
2
F
2
Chapter • Aspartic Protease Inhibitors
24
. Table 24.7 By modifying the R1 and R2 groups on 3,4-diaminopyrrolidine 24.44, the afnity and resistance prole is improved (wt
wild type; I84V mutant)
Compound R1 R2
24.47
24.48
24.49
24.50
24.51
Kt [mM] wt Kt [mM] I84V
2.15 1.7
12.3 84.0
74.7 53.1
1.57 5.82
0.67 0.46
24.52
24.53
24.54
24.55
24.56
24.57
24.58
0.77 0.47
0.46 0.55
0.39 0.33
C
3
0.80 0.50
0.27 0.13
NH
0.26 0.04
CONH
C
3
CONH
0.07 0.01
. • Synopsis
. Fig. 24.25 Compared to all of the currently marketed HIV inhib-
itors (. Fig.24.15, beige), the inhibitors based on 3,4-diaminopyrrolidine 24.44 (light green) adopt adeviating binding mode. As aresult,
adifferent activity prole against resistant mutants is observed
(Ki = 9.6 μM for HIV protease; . Fig.24.24, lower right).
As expected, the basic nitrogen atom binds between the
two aspartic acids, but at an H-bonding distance to only
one of the two aspartic acids. Interestingly, the structural water returns to the inhibitor complex and mediates
abinding contact between the two sulfonyl group and the
residues of the ap region.
The study of the open-chain compounds illustrates
how the sterically xed heterocycle determines the orientation of the inhibitors in the binding pocket. Its spatial demand is responsible for the displacement of the
structural water from the binding pocket. As aresult,
the H-bond acceptor groups of the inhibitors interact
directly with the ap region. The open-chain compound
24.59 gives the impression of tting perfectly into the
protease. It appears to lie completely relaxed in the
binding pocket, nding partners for its polar groups in
the protein and allowing the structural water to return.
Although it has amino groups in the para-position of
the benzenesulfonic acid group, which led to atenfold
increase in activity in the series with the 24.44 scaffold
(. Fig.24.22), it binds with only micromolar afnity.
Even the most beautiful binding mode will not help if
the open-chain compound must rst be conformationally
reorganized to adopt the necessary geometry at the site
of action. It loses too many degrees of freedom around
rotatable bonds, and this is ahigh price to pay in terms
of binding afnity (Sect.4.10). The open-chain compounds suffer from this disadvantage. This emphasizes
that properly pre-organized and rigidied inhibitors will
have aclear advantage for entropic reasons.
24.7 Other Targets from the Family
of Aspartic Proteases
In addition to the two examples of renin and HIV protease, many other members of the aspartic protease family have been validated as targets for drug development.
First, cathepsinD, aprotein involved in protein catabolism, appeared interesting and concepts for the treatment
of breast cancer or muscular dystrophy were pursued.
The aforementioned gastric pepsin was discussed as
apossible therapeutic target for peptic ulcer disease. Se-
cretory aspartic proteases (SAPs) from Candida albicans
have been considered as possible target enzymes for the
treatment of fungal diseases.
The eld of β-secretase has been the focus of intense
drug development as it could lead to an effective Alzheimer’s therapy. The disease-causing β-amyloid protein,
which leads to dangerous deposits (senile plaques) in the
brain, is cleaved from alarger precursor, amyloid precursor protein (APP). In 1999, two proteases, β- and γ-secre-
tase, were reported. As membrane-bound proteases of
the aspartic protease family, they catalyze the release of
β-amyloid protein. They are also referred to as BACE-1
and -2, which is an abbreviation for beta-site APP-cleav-
ing enzymes. Drugs that inhibit these proteases could
prevent the accumulation of β-amyloid and, thereby, halt
the onset or progression of Alzheimer’s disease. From
a medicinal chemistry perspective, potent and orally
available inhibitors such as verubecestat were successfully
developed at Merck in the United States. However, the
subsequent clinical trials were discontinued in February
2018. Unfortunately, verubecestat was not convincing in
reducing cognitive decline in patients with mild to moderate Alzheimer’s disease. It is unclear why the expected
effect did not occur in humans in the studies.
Plasmepsins are being validated as additional aspartic
protease targets for therapy. They are used by the malaria
parasite in the food vacuole to degrade hemoglobin. The
parasite uses the components of hemoglobin as food.
Plasmepsins are used for the initial cleavage of hemoglobin and cleave the α-chain between Phe33 and Leu34.
Several plasmepsin isoforms are involved in further cleavage to larger peptide fragments. Ten of these aspartic
proteases have been found in the genome of the malaria
parasite Plasmodium falciparum. In addition, falcipains,
other cysteine proteases, and falcilysin, azinc protease,
are also involved in the degradation process. The plasmepsins show ahigh structural homology to cathepsinD.
First lead structures have been derived using principles
analogous to those of, for example, renin. Recent evidence suggests that malaria therapy based on protease
inhibitors of hemoglobin degradation would need to
inhibit several of the above enzymes simultaneously to
achieve efcient control of the parasite. It may, therefore,
be appropriate to develop pan-inhibitors for the simultaneous, selective silencing of several plasmepsins.
24.8 Synopsis
Aspartic proteases possess two facing aspartate res-
-
idues in their catalytic cleavage center. Awater mol-
Chapter • Aspartic Protease Inhibitors
24
ecule, located at the apex between both aspartates, is
polarized and nucleophilically attacks the carbonyl
carbon atom of the amide bond to be cleaved.
The cleavage reaction proceeds through atetrahedral
-
transition state with atemporarily formed geminal
diol structure. Peptidomimetic inhibitors imitate this
intermediate structure by using chemically stable
building blocks. Hydroxyl groups embedded into hy-
droxyethylene or statin moieties have been especially
used as transition state isosteres.
Aspartic proteases often cleave between hydropho-
-
bic amino acids. These residues cannot form strong
interactions to the specicity pockets of the protease
on both sides of the cleavage site. They bind through
multiple contacts, and the recognition pockets are
well formed on both sides.
Renin specically cleaves angiotensinogen to angio-
-
tensinI. Subsequently, this product is further cleaved
to the octapeptide angiotensinII, which stimulates
blood pressure to increase once recognized at its re-
ceptor. Renin exhibits alarge, virtually merged S1/S3
pocket. This gave rise to the design concept to bridge
P1/P3 substituents in the inhibitor aliskiren and to dis-
rupt its central peptide chain. Amore polar, orally
available antihypertensive agent resulted with good
duration of action.
HIV protease is aviral aspartic protease that cleaves
-
the incipient polypeptide chain into mature proteins
required for the life cycle of the virus. It is aC2 sym-
metric homodimer with astructural water molecule
mediating interactions between the bound substrates
and the ap region closing up the catalytic site.
Through systematic variations of the minimal sub-
-
strate and introduction of transition state isosters,
a variety of potent and selective drugs with pep-
tide-like scaffolds are available for therapy. Upon
administration, the virus becomes resistant through
mutational modications; meanwhile, exchanges have
been reported for nearly half of all amino acid posi-
tions.
Combination therapy, the so-called HAART strat
-
egy, is recommended for the treatment of HIV infec-
tions. This tries to achieve better suppression of viral
replication through simultaneous administration of
multiple inhibitors acting on different targets that are
crucial for the virus.
Multiple design attempts have been followed to depart
-
from peptide-like inhibitors to nonpeptidic structures.
To date, tipranavir is the only compound to be suc-
cessfully launched to the market that has acentral
hydroxypyrone building block. In recent years, many
scaffolds containing abasic nitrogen to address the
catalytic dyad have been proposed as novel building
blocks for the development of aspartic protease in-
hibitors.
Aside from renin and HIV protease, cathepsinD, β-
-
and γ-secretase, the parasitic plasmepsin proteases,
and the fungal secretory aspartic protease SAP have
been investigated as potential drug targets.
Bibliography and Further Reading
General Literature
W. J. Greenlee and A. E. Weber, Renin Inhibitors, Drugs, News & Per-
spectives, 4, 332–339 (1991)
S. H. Rosenberg, Renin Inhibitors, Prog. Med. Chem., 32, 37–144
(1995)
E. De Clercq, The design of drugs for HIV and HCV, Nat. Rev. Drug
Discov., 7, 1001–1018 (2007)
P. S. Anderson, G. L. Kenyon and G. R. Marshall, Eds., Therapeutic
Approaches to HIV, Persp. Drug Discov. Design, Vol. 1, ESCOM
(1993)
J. A. Martin, S. Redshaw and G. J. Thomas, Inhibitors of HIV Protein-
ase, Prog. Med. Chem., 32, 239–288 (1995)
C. Hutchins and J. Greer, Comparative Modeling of Proteins in the
Design of Novel Renin Inhibitors, Crit. Rev. Biochem & Mol. Biol.
26, 77–127 (1991)
E. De Clercq, Toward Improved Anti-HIV Chemotherapy: Therapeutic
Strategies for Intervention with HIV Infections, J. Med. Chem., 38,
2491–2517 (1995)
E. De Clercq (Ed.) Antiviral drug strategies, 50th edn, Methods and
principles in medicinal chemistry. Wiley-VCH, Weinheim (2011)
M. L. West and D. P. Fairlie, Targeting HIV-1 Protease: A Test for
Drug-Design Methodologies, Trends Pharm. Sci., 16, 67–74 (1995)
R. E. Babine and S. L. Bender, Molecular Recognition of Protein–Li-
gand Complexes: Applications to Drug Design, Chem. Rev., 97,
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cure of HIV infection. Nat. Rev. Microbiol., 21, 657–670 (2023)
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A. K.Ghosh (Ed.) Aspartic acid proteases as therapeutic targets, Vol.
45, Methods and principles in medicinal chemistry. Wiley-VCH,
Weinheim (2010)
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-
A. R. Sielecki, A. A. Fedorov, A. Boodhoo, N. S. Andreeva, M. N. G.
James, Molecular and crystal structures of monoclinic porcine pepsin rened at 1.8 Å resolution, J. Mol. Biol., 214, 143–170 (1990)
H. Umezawa etal., Pepstatin, a new Pepsin Inhibitor produced by Ac-
tinomycetes, J. Antibiotics, 23, 259–262 (1970)
A. R. Sielecki etal., Structure of Recombinant Human Renin, a Target
for Cardiovascular-Active Drugs, at 2.5 Å Resolution, Science, 243,
1346–1351 (1989)
J. Rahuel, J. P. Priestle, M. G. Grütter, The crystal structures of recom-
binant glycosylated human renin alone and in complex with a transition state analog inhibitor, J. Struct. Biol., 107, 227–236 (1991)
B. L. Sibanda, T. Blundell, P. M. Hobart, M. Fogliano, J. S. Bindra, B.
W. Dominy, J. M. Chirgwin, Computer graphics modelling of human renin. Specicity, catalytic activity and intron-exon junctions,
FEBS Lett., 174, 102–111 (1984)
C. Frazao, C. Topham, V. Dhanaraj, T. L. Blundell, Comparative mod-
elling of human renin: A retrospective evaluation of the model
with respect to the X-ray crystal structure, Pure & Appl. Chem.,
66, 43–50 (1994)