Determinants of the Inhibition of DprE1 and CYP2C9 by Antitubercular Thiophenes

Article abstract of DOI:10.1002/anie.201707324

Mycobacterium tuberculosis (Mtb) DprE1, an essential isomerase for the biosynthesis of the mycobacterial cell wall, is a validated target for tuberculosis (TB) drug development. Here we report the X-ray crystal structures of DprE1 and the DprE1 resistant mutant (Y314C) in complexes with TCA1 derivatives to elucidate the molecular basis of their inhibitory activities and an unconventional resistance mechanism, which enabled us to optimize the potency of the analogs. The selected lead compound showed excellent in vitro and in vivo activities, and low risk of toxicity profile except for the inhibition of CYP2C9. A crystal structure of CYP2C9 in complex with a TCA1 analog revealed the similar interaction patterns to the DprE1–TCA1 complex. Guided by the structures, an optimized molecule was generated with differential inhibitory activities against DprE1 and CYP2C9, which provides insights for development of a clinical candidate to treat TB.

Full text of DOI:10.1002/anie.201707324

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Accepted Article
Title: Determinants of the Inhibition of DprE1 and CYP2C9 by
Antitubercular Thiophenes
Authors: Renhe Liu, Xiaoxuan Lyu, Mei-Hui Hsu, Catherine Vilcheze,
Scott G. Franzblau, William R. Jacobs, Gurdyal S. Besra, Eric
F. Johnson, Klaus Fütterer, and Feng Wang
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COMMUNICATION
Determinants of the Inhibition of DprE1 and CYP2C9 by
Antitubercular Thiophenes
Renhe Liu, [+] [a] Xiaoxuan Lyu, [+] [a] Sarah M Batt, [b] Mei-Hui Hsu, [c] Michael B Harbut, [a] Catherine
Vilchèze, [d] Bo Cheng, [a] Kehinde Ajayi, [a] Baiyuan Yang, [a] Yun Yang, [a] Hui Guo, [a] Changyou Lin, [a]
Fei Gan, [a] Chen Wang, [a] Scott G. Franzblau, William R. Jacobs Jr., Gurdyal S Besra, Eric F.
[e]
[d]
[b]
[
c]
[a]
[a]
[b]
[a]
Johnson, Mike Petrassi, Arnab K. Chatterjee, Klaus Fütterer, and Feng Wang*
Abstract: Mycobacterium tuberculosis (Mtb) DprE1, an essential
isomerase for the biosynthesis of the mycobacterial cell wall, is a
validated target for tuberculosis (TB) drug development. Here we
report the X-ray crystal structures of DprE1 and the DprE1 resistant
mutant (Y314C) in complexes with TCA1 derivatives to elucidate the
molecular basis of their inhibitory activities and an unconventional
resistance mechanism, which enabled us to optimize the potency of
the analogs. The selected lead compound showed excellent in vitro
and in vivo activities, and low risk of toxicity profile except for the
inhibition of CYP2C9. A crystal structure of CYP2C9 in complex with
a TCA1 analog revealed the similar interaction patterns to the DprE1-
TCA1 complex. Guided by the structures, an optimized molecule was
generated with differential inhibitory activities against DprE1 and
CYP2C9, which provides insights for development of a clinical
candidate to treat TB.
in vivo activities against Mtb, further validating DprE1 as an
attractive anti-tuberculosis (TB) drug target.[
5]
We previously reported the identification of TCA1 from a cell-
based phenotypic screen, and demonstrated it is a DprE1
inhibitor.[ Since then we have generated new derivatives of
TCA1 to improve its in vitro potency, PK properties, and in vivo
efficacy. When analyzing toxicity profiles, we noticed that many
TCA1 analogs show inhibition of CYP2C9, one of six major
cytochrome P450 enzymes which determine the clearance of
75% of marketed drugs. Therefore, inhibition of P450 enzymes
such as CYP2C9 can potentially lead to drug-drug interactions,
which may cause serious issues for combinatory drug regimen for
TB treatment.[
6]
7]
Here we report the X-ray crystal structures of WT DprE1, a TCA1-
resistant DprE1 mutant, and CYP2C9 in complex with TCA1
analogs. Along with structure activity relationship studies, the
mechanism of resistance by the mutant DprE1 enzyme and the
tight correlation between DprE1 and CYP2C9 inhibition was
elucidated. We further generated analogs with excellent in vitro
and in vivo activities against Mtb, and selectively targeting DprE1
over CYP2C9.
Mtb Decaprenylphosphoryl-β-D-ribofuranose 2-oxidase (DprE1)
is a flavin adenine dinucleotide (FAD)-dependent enzyme, which
together with decaprenylphosphoryl-D-2-ketoerythropentose
reductase (DprE2), converts decaprenylphosphoryl-beta-D-
ribose (DPR) to decaprenylphosphoryl-beta-D-arabinofuranose
(
DPA), an essential cell wall component.[1] Conditional
knockdown studies showed that loss of dprE1 results in a strong
bactericidal effect in vitro. Multiple covalent [3] and non-covalent
[
2]
[
4]
DprE1 inhibitors have been identified and showed in vitro and
[
a]
R. Liu[+], X. Lyu[+], M. B. Harbut, B. Cheng, K. Ajayi, B. Yang, Y.
Yang, H. Guo, C. Lin, F. Gan, C. Wang, M. Petrassi, A. K.
Chatterjee, F. Wang
California Institute for Biomedical Research (Calibr)
La Jolla, California 92037, United States
E-mail: fwang@calibr.org
[
[
+]
b]
These authors contributed equally.
S. M. Batt, G. S. Besra, K. Fütterer
School of Biosciences
University of Birmingham,
Birmingham B15 2TT, United Kingdom
M. Hsu, E. F. Johnson
Department of Molecular Medicine
The Scripps Research Institute,
La Jolla, California 92037, United States
C. Vilchèze, W. R. Jacobs. Jr.
[
c]
d]
[
Howard Hughes Medical Institute
Department of Microbiology and Immunology
Albert Einstein College of Medicine
Bronx, NY 10461
Figure 1. SAR optimization strategy for TCA1 analogs. Benzothiazole core
(red), thiophene carboxamide (green) and acylcarbamate (blue).
[e]
S. G. Franzblau
Institute for Tuberculosis Research, College of Pharmacy
University of Illinois
In the DprE1-TCA1 structure, TCA1 showed
a
planar
Chicago, IL 60612
conformation and tight fit in the DprE1 active site. The
benzothiazole core is oriented parallel to the FAD isoalloxazine
ring and the thiophene carboxamide resides in small hydrophobic
pocket. Besides substantial hydrophobic interactions, multiple
Supporting information for this article is given via a link at the end of
the document.
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COMMUNICATION
hydrogen bonding interactions are formed between TCA1 and
residues Lys418, His132, and Ser228 (Figure S1). Guided by the
structure, our medicinal chemistry effort focused on the
benzothiazole core (red), thiophene carboxamide (green) and the
acylcarbamate (blue) of TCA1 (Figure 1).
benzothiazole ring (TCA007) improved the IC50 by 8-fold (5 ± 2
nM) compared to TCA1 (48 ± 14 nM) (Figure 1, Table1, SI
methods and Figure S2-4).
The thiophene ring is located in a hydrophobic pocket formed by
Gly133, Lys367, Phe369 and Asn385 and accepts a H-bond from
His132 N2 (3.2 Å). Replacement of thiophene with other
heterocycles or adding bulky substitutions resulted in reduced
activity against Mtb (data not shown). Only a fluoro substituent on
the thiophene afforded an analog (TCA481) that is 5-fold more
potent than TCA1 based on MIC (Figure 1 and Table 1). To better
understand the basis of the activity increase, we solved the crystal
structure of DprE1 in complex with TCA481 (Table S1). The
structure reveals that the fluoro group forms a H-bond with
Asn385 N2 (3.4 Å). The fluorine is accommodated in the pocket
with stronger hydrophobic interactions with residues Phe369,
His132, and Lys367 than TCA1 (Figure 2B and Figure S1).
Table 1. Correlation between inhibition on DprE1 WT and mutant enzyme
activity and cellular potency by TCA1 and analogs (μM)[
.
4d]
TCA1
analogs
IC50
WT
DprE1
IC50 DprE1
Y321C
MIC WT
MIC
Y314C
[a]
[a]
TCA1
0.048±0.014
0.0053±0.18
ND
0.37±0.13
0.24±0.052
0.13±0.021
ND
>10
1.8±0.54
0.23±0.012
0.089±0.0066
0.046±0.0025
2.5±0.48
5.4±0.32
2.4±0.34
1.4±0.086
17±1.1
TCA007
TCA481
TCA020
TCA787
[
b]
[b]
0.096±0.038
0.44±0.12
14±1.4
[
a] All in vitro assays were performed using M. smegmatis DprE1 which
shows 83% sequence identity with Mtb DprE1. M. smegmatis Y321C
corresponds to Y314C in Mtb. [b] IC50 of TCA481 was not determined due
to its low solubility under the assay condition.
Modification of the carbamate group was carried out; however,
most of the analogs such as amides and esters are not active,
demonstrating the importance of hydrogen bonding between
Ser228 and the carbamate group (3.0 to 3.5 Å) (Figure 2C and
Figure S1). When replacing the carbamate with various
heterocycles, only TCA020 with pyrimidine showed moderate
activity (MIC = 2.5 M, IC50 = 370±133 nM) (Figure 1 and Table
1). To help optimizing the pyrimidyl substituent, we crystallized
DprE1 in complex with TCA020 (SI methods). The DprE1-TCA1
structure revealed that the two nitrogen atoms of the pyrimidine
ring occupy the positions of the two oxygens of the carbamate
group as H-bond acceptors. Based on these structural insights,
we introduced a methyl group at 4-position of the pyrimidine to
gain a hydrophobic interaction with W230 (TCA787), which has
similar activity to TCA1 (Figure 1 and Table 1).
Y314 resides close to the carbamate moiety and it was previously
found that a spontaneous TCA1 resistant mutant harbors a
Y314C mutation.[6] We measured the inhibitory activities of TCA1
and its analogs against DprE1 and the Y314C variant and
observed 5- to 40- fold shift on IC50 values under the same assay
condition, which is consistent with the MIC shift between the
wildtype (WT) and the mutant strain (Table 1). These data
support the notion that growth inhibition of Mtb by the TCA1 series
of inhibitors is via DprE1 inhibition. We also generated a Y314A
mutant and it is sensitive to TCA1 inhibition, suggesting that the
side chain of Y314 does not directly contribute to TCA1 binding
Figure 2. Non-covalent interactions of TCA inhibitors with DprE1. (A)
Inhibitor TCA020 (pink) with non-covalent interactions indicated in dashed lines
(magenta). The unbiased Fo – Fc density map (contoured at 2.5 σ) was
(
Table S2). To elucidate the molecular basis of the resistance
calculated with model phases prior to incorporation of the ligand in the structural
model. Protein residues are shown in grey sticks, FAD in yellow sticks. (B, C)
Superposition of TCA1 with the inhibitors TCA481 and TCA020, respectively.
Dashed lines in cyan indicate new or shortened non-covalent interactions
compared to the TCA1:wt-DprE1 complex (see Figure S1 for contact distances).
Protein side chains in green indicate amino acids that – in TCA1:wt-DprE1 – fall
outside the 4 Å contact radius. (D) The flipped orientation of TCA1 (cyan) in the
DprE1-Y314C active site.
mechanism, the structure of DprE1 Y314C bound with TCA1 was
determined to 2.2 Å. (Figure 2D, Figure S1 and Table S1).
Although the overall fold of the mutant enzyme is identical to
wildtype, consequential structural changes in the active site of
DprE1 were evident. The most striking difference between the WT
and mutant DprE1 complexes is the 180º flipped orientation of the
boomerang-shaped ligand in the active site (Figure S1 and Figure
S5). The alternative orientation of the ligand can be linked to the
effects of cysteine 314 substitution on the orientation of Lys134,
which positions the ε-ammonium group in the void created by
substituting the tyrosyl ring with a thiol. The reorientation of
Lys134 is driven by formation of a strong H-bond (2.75 Å)
between its ε-ammonium and the thiol of Cys314 and results in a
The Gln334 amide group and the Tyr60 hydroxyl group are only
3.7 Å away from C4 and C5 of the TCA1 benzothiazole ring,
respectively, which make them two potential H-bond donors if H-
bond acceptors are introduced at these positions (Figure 1 and
Figure S1). Indeed, the introduction of nitrogen to the
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noticeable shape change of the active site around Lys134.
Consequently, the acylcarbamate keto-oxygen in the original
orientation would clash with the alkyl moiety of Lys134 (with the
shortest distance at 2.7 Å), which likely weakens the binding of
TCA1 (Figure S5).
of the heme cofactor where the reactive oxidant is formed, thus
preventing oxygenation of the thiophene moiety. The pocket is
formed by the inner surface of helix B' and adjacent residues
(Figure 4A) and hydrophobic residues on helix F across from B'
and helix G above TCA007. Mimicking the role of DprE1 Lys418,
Arg108 donates H-bonds from N to the carbonyl oxygen of the
thiophene carboxamide (3.0 Å) and from N2 to the thiazole
nitrogen (3.4 Å). The thiophene carbonyl also accepts an H-bond
from a water molecule. The Arg108 N also contacts the
thiophene sulfur. Arg108 plays a critical role in recruiting
negatively charged or partially charged substrates such as
diclofenac and warfarin, respectively, to the substrate binding site
of 2C9. Substitution of Arg108 by alanine[12], histidine or
phenylalanine[13] leads to a loss catalytic activity for the two
substrates.
Due to its superior activity against Mtb and improved PK
properties, TCA007 was selected as a lead compound for further
investigation. We evaluated the efficacy of TCA007 against Mtb
Erdman in acute and chronic BALB/c mouse low dose aerosol
infection models [8]. After treatment for 3 weeks during the acute
phase of infection with TCA007 at a dose of 50 mg/kg and 100
mg/kg body weight, a dose-dependent in vivo efficacy was
observed with reduction of bacterial load in lung by 1.7 and 2.3
log10 CFU, respectively (Figure 3A and SI methods). This
excellent in vivo bactericidal activity is comparable to the first-line
drug rifampin. Following 4 weeks of treatment during the chronic
phase of infection, TCA007 at 200 mg/kg achieved a reduction of
A
>1.7 log10 CFU in mouse lungs (Figure 3B).
A
B
7
6
5
4
3
2
1
0
7
6
5
4
3
t
trl
)
)
)
t
l
r
t
)
)
0
n
h
5
0
0
0
n
5
e
e
C
a
(1
5
0
e
C
(1
0
2
(
1
m
V
e
in
T
7
(
tm
le
in
(
7
t
l
0
T
7
a
ic
p
0
0
a
ic
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e
ifa
A
-
e
i
f
C
C
A
re
V
C
r
R
R
T
P
P
B
C
Figure 3. In vivo efficacy study. A. efficacy of TCA007 in a mouse acute model
of established TB. B. efficacy of TCA007 in a mouse chronic model of
established TB. The in vivo dose (mg/kg) of each compound is shown in
parentheses.
A typical treatment of TB lasts for more than six months, and
therefore, the safety profile of anti-TB drugs is of great importance.
TCA007 is not cytotoxic against Vero and HepG2 cell lines at up
to a concentration of 100 μM. TCA007 does not inhibit hERG
D
potassium channel in a patch-clamp assay (IC50
> 30 μM),
suggesting a low risk of cardiotoxicity. In addition, we observed
no genetic toxicity in a mini-Ames mutagenicity test. TCA007
showed no inhibition of four major CYPs, 1A2, 3A4, 2D6, 2C19,
but a strong inhibitory effect for CYP2C9 (SI methods).
The potent inhibition of P450 2C9 could reflect oxygenation of
thiophene moiety of TCA analogs to an electrophilic S-oxide or
epoxide[ that reacts with the enzyme to form an irreversible
inhibitor as seen for tienilic acid.[10] However, the inhibition of 2C9
by TCA analogs was not time dependent indicating a reversible
mode (Figure S6). To better understand the interactions of
TCA007 with 2C9, the structure of the complex was determined
by X-ray crystallography to 2.0Å resolution[11] (PDB: 5W0C) (SI
methods, Table S3 and Figure S7). Similar to the binding of TCA1
to DprE1, the thiophene group of TCA007 binds in a hydrophobic
pocket of the 2C9 substrate binding cavity that is far from the iron
9]
Figure 4. Crystal structure of CYP2C9 with TCA007. A. Key interactions
exhibited by TCA007 (violet carbons) in the CYP2C9 active site (PDB:5W0C).
Amino acid side-chains that contact TCA007 are rendered as sticks. The red
spheres are water molecules, and the dashed lines depict H-bonds. B. and C.
Modeling TCA711 (cyan) in the CYP2C9 structure (overlap with TCA007 in
violet) (B) and DprE1 structure (overlap with TCA1 in megenta) (C). D. SAR
optimization strategy for TCA1.
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Phe100, Leu102, and Phe114 form a hydrophobic pocket
together with Phe476 where the carbamate group of TCA007 is
bound (Figure 4A). In contrast to DprE1, protein H-bond donors
for the carbamate are not present in this pocket, but the cavity is
open to solvent and an ordered water molecule donates an H-
bond to the carbonyl of the acyl group. The pyridyl nitrogen of the
pyridothiozole group is oriented toward the heme but is too distant
inhibitors but revealed an unconventional resistant mechanism of
DprE1. The optimized lead compound TCA007 showed excellent
in vitro and in vivo activities, PK properties, and low risk of toxicity
profile except for the strong inhibition of CYP2C9. Guided by the
structures of CYP2C9 in complex with TCA1 analogs, an
optimized molecule, TCA711, was generated with differential
inhibitory activities against DprE1 and CYP2C9, which paved the
road for further development of a clinical candidate to treat TB.
(
6.6Å) for coordination to the heme iron. Consistent with this
observation, TCA007 does not significantly alter the visible
absorption spectrum of 2C9 in solution. In contrast, miconazole
binds to the heme iron of 2C9 and alters the spectrum of the heme
co-factor, and competitive displacement of iron bound miconazole
by TCA007 reverts the spectrum of the miconazole complex to
that of the apo enzyme (Figure S8). This portion of the active site
is also hydrophobic, but a molecule of water is evident 2.88Å from
the pyridyl nitrogen of TCA007 (Figure 4A). The water molecule
is hydrogen bonded to a second water molecule that donates a
lone pair of electrons to the heme iron and a H-bond to the
Acknowledgements
The authors thank Dr. Stewart Cole and GSK for providing DprE1
substrate FPR. The authors also thank Drs. Cliff Barry and Tanya
Parish, Katarina Mikusova, and Danling Wang for technical
support or helpful discussion. This work was supported, in part,
by the Bill and Melinda Gates Foundation, the Global Alliance for
TB Drug Development, and NIH Grants AI0–51519 (WRJ),
GM031001 (EFJ), a Personal Research Chair from Mr James
Bardrick and a Royal Society Wolfson Research Merit Award
backbone carbonyl of Ala297.
In general, the extensive
hydrophobic interactions and hydrogen bonding interactions with
Arg108 are likely to form the basis for the high affinity, reversible
binding of TCA007 to 2C9, but these interactions also sequester
TCA007 in position that reduces the likelihood of metabolism,
which is consistent with absent or low rates of metabolite
formation or time dependent inhibition.
(
GSB), MRC (MR/K012118/1) (GSB and KF), the Diamond Light
Source (proposal number MX8359), and the Stanford
Synchrotron Radiation Lightsource (DE-AC02-76SF00515 and
NIH P41GM103393).
Keywords: DprE1 • CYP2C9 • anti-tubercular drugs • drug-drug
interactions • drug development
Removal of these aforementioned heteroatoms will likely reduce
the CYP2C9 inhibition. However, it was shown that the thiophene
group and carbonyl group are also essential for DprE1 binding.
Therefore, we instead modified the ring A to reduce CYP2C9
inhibition while gaining extra interactions in ring B to maintain
DprE1 binding (Figure 4B). Both sulfur and nitrogen in the ring A
were removed to reduce the interaction in CYP2C9, and two
nitrogens were introduced into ring B which potentially form H-
bonds with Tyr60 and Glu334 to compensate for the reduced
interaction in DprE1 (Figure 4C). The IC50 ratio (CYP2C9 over
DprE1) for TCA582 and TCA711 were 33 and 1515, respectively,
[
[
1]
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a
1, 615; e) J. Neres, R. C. Hartkoorn, et al., ACS Chem. Biol. 2015,
significant improvement in selectivity (Figure 4D). The modeling
of CYP2C9 with both TCA582 and TCA711 revealed that the
carbamate group could gain favorable hydrophobic interactions
with Phe100 (3.6Å), Phe114 (4.1Å) and Phe476 (3.8Å). These
interactions would be weakened by an unfavorable hydrophobic
interaction with Phe100 (2.9 Å and 3.0Å) when replacing the
carbamate with pyrimidyl substituent, which could explain the
nearly eliminated inhibition of CYP2C9 by TCA711 (IC50 of
CYP2C9 > 50 uM) (Figure 4D). The in vivo studies on the
advanced analog TCA711 are ongoing.
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In summary, we demonstrate the mode of inhibition of DprE1 by
the thiophene scaffold via enzymatic and structural studies. The
SAR studies not only helped us to optimize the potency of the
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Entry for the Table of Contents (Please choose one layout)
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Text for Table of Contents
Renhe Liu, Xiaoxuan Lyu, Sarah M Batt,
Mei-Hui Hsu, Michael B Harbut,
The structures of DprE1 and CYP2C9
in complex with inhibitors, respectively,
revealed a similar pattern of
interactions between the two enzymes
and the inhibitors. Guided by the
structures, an optimized thiophene
analog was designed and generated
with more selective inhibitory activity
against DprE1 than CYP2C9.
Catherine Vilchèze, Bo Cheng, Kehinde
Ajayi, Baiyuan Yang, Yun Yang, Hui Guo,
Changyou Lin, Fei Gan, Chen Wang,
Scott G. Franzblau, William R. Jacobs
Jr., Gurdyal S Besra, Eric F. Johnson,
Mike Petrassi, Arnab K. Chatterjee, Klaus
Fütterer, and Feng Wang*
Cyp2C9
DprE1
Page No. – Page No.
Determinants of the Inhibition of
DprE1 and CYP2C9 by Antitubercular
Thiophenes
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