Discovery of Novel Neuraminidase Inhibitors by Structure-Based Virtual Screening, Structural Optimization, and Bioassay

Article abstract of DOI:10.1021/acsmedchemlett.9b00447

Neuraminidase (NA) is a significant therapeutic target for treating influenza. In this study, a new lead NA inhibitor AN-329/10738021 was discovered by structure-based virtual screening, molecular dynamics simulations, and bioassay validation. Optimization of lead AN-329/10738021, which holds a novel scaffold of N′-benzylidene benzohydrazone, leads to discovery of some novel NA inhibitors Y-1-Y-11. Compound Y-1 exerts the best inhibition activity (IC₅₀ = 0.21 μM) against NA, which is better than oseltamivir carboxylate (OSC) (IC₅₀ = 3.04 μM) and lead AN-329/10738021 (IC₅₀ = 1.92 μM). Molecular docking analysis indicates that the good potency of Y-1 may be ascribed to the elongation of the benzylidene moiety of the molecule to the 430-cavity. The results of this study may offer useful reference for development of novel NA inhibitors.

Full text of DOI:10.1021/acsmedchemlett.9b00447

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Letter
Discovery of novel neuraminidase inhibitors by structure-
based virtual screening, structural optimization, and bioassay
Rao Yu, Li Ping Cheng, Meng Li, and Wan Pang
ACS Med. Chem. Lett., Just Accepted Manuscript • DOI: 10.1021/acsmedchemlett.9b00447 • Publication Date (Web): 25 Nov 2019
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Discovery of novel neuraminidase inhibitors by structure-based vir-
tual screening, structural optimization, and bioassay
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Rao Yu, Li Ping Cheng*, Meng Li, Wan Pang
*School of Chemical and Environmental Engineering, Shanghai Institute of Technology, Shanghai 201418, China
KEYWORDS: Virtual screening; neuraminidase; inhibitors; bioassay.
ABSTRACT: Neuraminidase (NA) is a significant therapeutic target for treating influenza. In this study, a new lead NA inhibitor
AN-329/10738021 was discovered by structure-based virtual screening, molecular dynamics simulations, and bioassay validation.
Optimization of lead AN-329/10738021, which holds a novel scaffold of N’-benzylidene benzohydrazone, leads to discovery of some
novel NA inhibitors Y-1-Y-11. Compound Y-1 exerts the best inhibition activity (IC50=0.21 µM) against NA, which is better than
oseltamivir carboxylate (OSC) (IC50 =3.04 µM) and lead AN-329/10738021 (IC50 =1.92 µM). Molecular docking analysis indicates
that the good potency of Y-1 may be ascribed to the elongation of benzylidene moiety of the molecule to the 430-cavity. The results
of this study may offer useful reference for development of novel NA inhibitors.
Influenza virus belongs to the Orthomyxoviridae family. It
can be classified as four types (A, B, C and D) according to the
antigenicity of nucleoprotein. As the main pathogen of human
influenza, influenza A is often prone to cause influenza outbreak
or pandemic. Influenza A virus is an enveloped negative-strand
RNA virus. Its genome, which encodes up to 11 proteins, com-
prises eight viral RNA (vRNA) segments (PB2, PB1, PA, HA,
NP, NA, M, and NS). 1-2 The base of single-stranded RNA is
unstable and more likely to mutate than double-stranded.
What’s more, gene exchange, deletion and addition may occur
between different eight RNA segments, which may lead to gene
recombination. Therefore, the development of highly efficient
anti-influenza drugs, which are insusceptible to virus mutation,
is particularly important.
In this research, the discovery of novel NA inhibitors was per-
formed by structure-based virtual screening, molecular dynam-
ics (MD) simulations, chemical synthesis and bioassay. A novel
lead compound was firstly hit by virtual screening, then the lead
compound was used as template to design some new NA inhib-
itors targeting the 430-cavity. Finally, the designed 11 new in-
hibitors were synthesized and tested for biological activity.
Neuraminidase (NA), a surface glycoprotein in influenza vi-
rus, plays crucial rule in viral replication and infection and is a
validated target for design of anti-influenza drugs.3-4 Currently,
the first-choice anti-influenza drugs recommended for treating
influenza virus are NA inhibitors, such as oseltamivir and
zanamivir.5 Though these antiviral drugs are efficient against
the current influenza virus strains, their use can lead to the oc-
currence of drug-resistant virus.6
Recently, a new pocket named “430-cavity”, which is adja-
cent to the active site of the NA, attracts great attention. 430-
cavity has large molecular volume and connects directly to ac-
tive site, which makes it a promising binding site for inhibitor
design. What’s more, 430-cavity widely exists in various sub-
types of influenza virus, and NA inhibitors designed based on
430-cavity have broad spectrum.7 Some research groups have
designed some new NA inhibitors based on 430-cavity, and
have achieved good results. For example, Ju et al.7 had discov-
ered a series of novel oseltamivir derivatives targeting the 430-
cavity. Zhu et al.8 had designed and synthesized a series of novel
analogues of zanamivir as NA inhibitors. The good inhibitory
activity may be ascribed to the elongation of the C-1- groups of
the molecules to the 430-cavity.
Figure 1. Structures of representative NA inhibitors
In this paper, 10 typical NA inhibitors (shown in Fig.1) were
picked out to generate pharmacophore models from different
references.9-13 And the pharmacophore models were constructed
by GALAHAD module of SYBYL-X 2.1 package (Tripos Inc.
St. Louis, USA). The obtained 20 pharmacophoric models were
validated by performing Güner-Henry (GH) test.14 The GH test
set contains 78 active molecules and 100 inactive molecules.
The best pharmacophoric model hits a total of 79 molecules in
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the GH test set, which includes 76 active and 3 inactive mole-
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cules. The GH test score was 0.94, a threshold value considered
as an excellent model, implying that this pharmacophoric model
can be used to screening.15-17 The detailed statistical parameters
are shown in Table 1.
MD
SPECS
Database
Molecular
Docking
(100)
Pharmacophore
Model
Bioassay
Hit
(1)
Simulation
(10)
Table 1. The detailed statistical parameters of the best phar-
macophore model based on the GH Test
(5)
(774)
(212,713)
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parameters
value
178
78
total molecules in test set (D)
total number of actives in test set (A)
total hits (Ht )
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Figure 3. Workflow of the virtual screening process.
Subsequently, molecular docking18 had been carried out for
Database 2 to study the binding modes between inhibitors and
NA crystal structures (PDB ID: 2HU0). As a result, the top 100
compounds with higher docking scores and binding modes close
to that of the original extracted ligand with 2HU0 were screened
out to compose Database 3. By carefully analysis of the spatial
matching and interactions between the 100 compounds and NA
protein, 10 compounds with higher total score values were se-
lected to form Database 4 for further study. The structures of
the 10 compounds are shown in Fig. 4 (SPECS-1-SPECS-5)
and Fig. S1 (SPECS-6-SPECS-10).
active hits (Ha )
76
%Y, yield of actives [(Ha /Ht ) × 100]
% A, ratio of actives [(Ha /A) × 100]
enrichment factor (EF) a
GH test score b
96.2
97.4
2.20
0.94
a EF = (Ha D)/(Ht A). b GH test score = [Ha (3A + Ht )/(4Ht
A)][1 -(Ht - Ha )/(D - A)].
The characteristics of the best pharmacophoric model was
shown in Fig. 2, including two positive nitrogen (NP_2, NP_3),
two donor atoms (DA_1, DA_4), two hydrophobic centers (HY-
7, HY-8), two acceptor atoms (AA-5, AA_6), and one negative
center (NC_9). As seen from Fig. 2A, the known inhibitor I (Fig.
1) was superimposed on the pharmacophoric features. The car-
boxyl of inhibitor I can be readily superimposed on negative
center (NC_9) and H-bond acceptor (AA_5). Cyclohexene ring
was superimposed on hydrophobic center (HY_7). The aliphatic
chain moiety of 3-(1-ethylpropoxy) makes it one hydrophobic
center (HY_8). The carbonyl group of acetylamino was super-
imposed on H-bond acceptor (AA_6). The two imino nitrogens
of guanidyl could be readily identified by features of NP_2 and
NP_3, respectively.
To discovery of novel lead compounds, MD simulations were
performed for 10 compounds in Database 4 by Amber 12.19 The
stability of the NA-inhibitor complex was determined based on
the root-mean-square deviation (RMSD)20 values of the accep-
tor backbone atoms (Fig. S2 and Fig. S3). The results show that
five compounds can well embed in the active site or 430-cavity
of the neuraminidase and have smaller binding energies com-
pared with the other five compounds. The predicted binding free
energies (ΔGbind) of the 10 compounds via Molecular Mechan-
ics/Generalized Born Surface Area (MM/GBSA)21 and Molec-
ular Mechanism/Poison-Boltzman Surface Area (MM/PBSA)22
methods are listed in Table S1 and Table S2. It is known that
there is generally a good correlation between binding free en-
ergy and compound’s activity. The more negative the ΔGbind of
compound is, the more active the compound is.21,22 By calcula-
tion of the binding free energies of the 10 compounds in Data-
base 4, and 5 compounds (SPECS-1-SPECS-5) with smaller
binding free energies were selected to make up Database 5.
Figure 2. Alignment known inhibitors I(A) and lead com-
pound AN-329/10738021(B) on derived pharmacophoric fea-
tures.
The workflow of virtual screening in this study is displayed
in Fig. 3. The large SPECS database, consisting of 212,713
small molecules, was selected for virtual screening in this work.
The best pharmacophoric model was used as a 3D query to
screen the SPECS database using the UNITY search engine in
SYBYL-X 2.1. 1024 molecules were hit. The Lipinski drug five
principles were used as filters to screen the drug properties of
the compound, and finally Database 2 (774 compounds) were
obtained.
Figure 4. Chemical structures and inhibitory activity of the
five NA inhibitors with their SPECS IDs.
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Then, the 5 compounds in Database 5 were bought from
target both the 430-cavity and the known active subsites. Herein
we designed and synthesized a series of lead compound analogs
(Y-1-Y11) with different substitutions at aryl B rings to explore
the 430-cavity.
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3
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5
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7
8
SPECS for further biological evaluation. OSC was selected as
the reference compound. The results show that five compounds
all exert good potency, with IC50 values of less than 20 μM (Fig.
4), Compound AN-329/10738021 has the best inhibitory activ-
ity (IC50=1.92 µM), which is better than OSC (IC50 =3.04 µM).
Moreover, among the five compounds, three compounds (AN-
329/10738021, AH-487/40686965, and AH-487/406867204)
with the lowest IC50 values all have the same skeleton structure
of N'-benzylidene benzohydrazone. Accordingly, compound
AN-329/10738021 could be used as a lead compound to per-
form further modification to obtain new inhibitors with good in-
hibition activity. As shown in Fig. 2B, lead compound AN-
329/10738021 was superimposed onto the pharmacophoric fea-
tures. Compared with the features in Fig. 2A, the 3,5-dihydroxy
substituted benzohydrazide makes the C-1 and C-2 position one
acceptor center (AA_5) and negative center (NC_9). Two posi-
tive nitrogen atoms of -C=N-NH- group could be readily iden-
tified by features of NP-2 and NP-3. The 5-nitrobenzylidene can
be readily superimposed on hydrophobic (HY_8) center. Con-
sequently, the lead compound was valuable for further study for
its good inhibitory activity.
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Figure 6. Schematic diagram of S1-S5 sites division and
binding mode of NA and sialic acid.23
Table 2. Activity of the Compounds Y-1-Y-11 in the Bioas-
say against NA
Compd
Y-1
IC50(μM)
0.21±0.04
3.71±0.53
5.47±1.32
3.97 ±0.55
14.83 ±3.76
11.64 ±2.41
1.92 ±0.41
Compd
Y-7
IC50(μM)
13.77±2.89
9.67 ±1.33
10.56 ±1.89
22.74±3.55
36.60±4.17
3.04±0.47
Y-2
Y-8
Y-3
Y-9
Y-4
Y-10
Y-11
OSC
Figure 5. The design of new inhibitors based on the lead
compound.
Y-5
Y-6
Leada
According to the features derived from the pharmacophoric
model and molecular docking results, some new NA inhibitors
(Y-1-Y-11) were designed (Table 2 and Scheme 1). Lead com-
pound AN-329/10738021 was used as template. The design idea
was summarized in Fig. 5. 430-cavity is mainly composed of
Trp403, Lys432, Ile427 and Thr439 etc, which could be re-
garded as a hydrophobic pocket. Therefore, some hydrophobic
groups, such as nitro groups (Y-1-Y-4) and methoxy groups (Y-
5, Y-6), were introduced to ring B expected to interact with 430-
cavity. It was revealed that the active site of NA could be em-
pirically divided into 5 regions, termed subsites S1-S5, that are
essential for the interactions with different NA inhibitors (Fig.
6).23 S1 site consists of three positively charged arginine resi-
dues (Arg118, Arg292 and Arg371), which can form very
strong electrostatic interactions with anionic substituents from
the inhibitor and provide hydrogen-bonding environment. S2
site is comprised of Glu119 and Glu227, which can form hydro-
gen bonds with basic groups. S3 site is a small hydrophobic re-
gion formed by the side chains of Trp 178 and Ile 222 adjacent
to a polar region provided by the side chain of Arg 152, which
can interact with various hydrophobic groups; S4 site is a hy-
drophobic region comprised of side chains of Ile 222, Ala 246,
and the hydrophobic face of Arg 224, which also can interact
with some hydrophobic groups. S5 is a mixed polarity region
formed from the carboxylate of Glu 276 and the methyl of Ala
246, which may produce interactions with various groups by the
hydrophilic carboxyl of Glu276 and the hydrophobic methyl of
Ala246. The flexible 430-cavity is next to the subsite S1,8 which
can provide a large cavity adjacent to the active site. This pro-
vides a good chance to design highly novel NA inhibitors that
aLead is AN-329/10738021.
Compounds Y-1-Y-11 were synthesized by feasible synthetic
strategies in Scheme 1. Their activities against NA were further
biologically tested. The inhibitory profiles for in vitro tests are
displayed in Fig. S4. For comparison, lead compound AN-
329/10738021 and OSC were evaluated as the reference com-
pounds. As seen from Table 2, Compound Y-1 exhibits the most
potent inhibitory activity (IC50 =0.21 µM), which is better than
AN-329/10738021 (IC50 =1.92 µM) and OSC (IC50 =3.04 µM).
The activities of Y-2 (IC50 =3.71 µM), Y-3 (IC50 =5.47 µM) and
Y-4 (IC50 =3.97 µM) are comparable to that of OSC. It can be
seen that compounds with strongly electronegative groups (such
as nitro group and halogen atoms) in ring B show better inhibi-
tory activity, whereas the introduction of methoxy and amide
groups (Y-5-Y-7) in ring B maybe decrease the compounds’ ac-
tivity. As shown in Scheme 1, the only difference between Y-1-
Y-4 and Y-8-Y-11 is the existence of an additional hydroxy
group at the para-position of hydrazone group, which decreases
compounds’ activity. This trend could be rationalized with the
strong hydrophilicity of hydroxy group. Molecular docking
analysis indicates that the hydroxyl group of A ring at the para-
position of hydrazone group is close to S3 or S4 region of the
NA active site (see Fig. S5). Nevertheless, S3 and S4 are hydro-
phobic regions, which interact with hydrophobic groups well.
To better comprehend the differentiation of inhibitory activity
of Y-1, AN-329/10738021, and OSC, molecular docking was
carried out to study the binding modes between NA and inhibi-
tors. Fig. 7 shows the binding poses of Y-1, AN-329/10738021
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and OSC with NA (PDB 2HU0). The 3D figures of Y-1, lead
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may form three hydrogen bonds with residues Arg156 and
Glu119 of S2 site. Regarding the acylhydrazone moiety, for Y-
1, the carbonyl oxygen atom can form three hydrogen bonds
with residues Tyr406, Arg292 and Arg371 of S1 site, the double
bond nitrogen can form one hydrogen bond with Arg371; no
hydrogen bond is formed with the near residues for the lead AN-
329/10738021. In addition, the acylhydrazone group can form
other extensive interactions, such as van der Waals force and
carbon hydrogen bond with the around residues of the active site.
Comparison of Y-1 and AN-329/10738021, although the aryl B
ring may both interact with the 430-cavity, the introduced group
in Y-1 can enter deeper into the 430-cavity and it can form more
hydrogen bonds and stronger hydrophobic interactions with the
residues of 430-cavity, which may lead to its stronger inhibitory
activity compared with the lead AN-329/10738021. For OSC,
the deprotonated carboxyl may form multiple hydrogen bonds
with the near residues (Arg118, Arg292, Arg371, and Tyr347).
At the same time, it can form strong electrostatic interactions
with the three positively charged arginine residues (Arg118,
Arg292, Arg371) of S1 site. The carbonyl oxygen atom of acet-
ylamino may form one hydrogen bond with residue Arg152 of
S3 site. The cyclohexene ring and the aliphatic chain moiety of
3-(1-ethylpropoxy) may form strong hydrophobic interactions
with residues Trp178, Arg224, Ile222 of S3 and S4 sites. Alt-
hough OSC can well interact with NA active site, the docking
results show that it could not interact with the 430-cavity, which
perhaps leads to its weaker activity compared with Y-1 and the
lead AN-329/10738021.
1
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3
4
5
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7
8
compound (AN-329/10738021) and OSC had been aligned in
Fig. 8 to ensure that protein conformation is the same for all
three complexes. From Figures 7 and 8 it can be seen that the
rings A of Y-1 and AN-329/10738021, as well as the whole
skeleton of OSC can all well implant into the active site of neu-
raminidase. However, it is worth noting that the aryl B rings in
Y-1 and AN-329/10738021 could be elongated into the 430-
cavity, whereas the OSC could not reach 430-cavity.
From 2D figures one can see that the aryl B rings of Y-1 and
AN-329/10738021 were projected toward the 430-cavity to
form hydrogen bonds and hydrophobic interactions. For exam-
ple, for Y-1, the 3-nitro may form two hydrogen bonds with res-
idue Arg428 of 430-cavity. The 4-hydroxyl can form one hy-
drogen bond with residue Glu425. The aryl B ring can form ex-
tensive hydrophobic interactions with some key residues Ile427,
Pro431, and Lys 432 of 430-cavity. For the lead AN-
329/10738021, the aryl B ring may form hydrophobic interac-
tions with residues Ile427 and Pro431 of 430-cavity. The 5-nitro
may form three hydrogen bonds with residues Arg118 and
Arg371 of S1 site. Therefore, the good inhibition activity of Y-
1 and lead AN-329/10738021 may be attributed to their elon-
gated aryl B ring groups. The A ring moiety of Y-1 and AN-
329/10738021 can also interact with some active region of NA
active site. For example, the 3-hydroxyl of Y-1 may form one
hydrogen bond with the hydrophilic carboxyl of Glu276 of S5
site. The 3-hydroxyl of AN-329/10738021 may form one hy-
drogen bond with residue Glu227 of S2 region. The 5-hydroxyl
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Scheme 1. Synthesis of Compounds Y-1-Y-11
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Figure 7. Binding modes of OSC, AN-329/10738021 and Y-1 with NA (PDB 2HU0). Hydrogen bonds are indicated by green dot-
ted lines (for the hydrophobic surfaces on protein, brown represents the maximum hydrophobic, and blue represents the maximum
hydrophilic).
were calculated and shown in Table 3. In this research, ΔGbind
was calculated by MM/PBSA and MM/GBSA methods. The PB
model is theoretically more rigorous than the GB models, and
MM/PBSA is often considered to be naturally superior to
MM/GBSA in predicting binding free energies.24 As can be seen
from Tables 2 and 3, the smaller the ΔGbind of inhibitor-NA is,
the stronger the activity of the inhibitor is for most inhibitors.
For example, Y-1 has the lowest ΔGbind (-31.26 kcalmol-1) and
it exerts the best NA-inhibiting activity. What’s more, Y-2 (-
27.85 kcalmol-1), Y-3 (-21.87 kcalmol-1) and Y-4 (-18.41
kcalmol-1), which have better inhibitory activities, also have
lower ΔGbind values. The ΔGbind values of Y-1-Y-3 are all less
than -20.00 kcalmol-1. Y-5-Y-9 have similar inhibitory activi-
Figure 8. Proposed binding modes of Y-1, AN-329/10738021
and OSC in the active site of NA (PDB 2HU0).
ties and their IC50 values are about 10.00 µM. And their ΔGbind
values are between -15.00 and -20.00 kcalmol-1 except Y-6. Y-
10 and Y-11 have poor activity in inhibition of NA, especially
MD simulations were also carried out for all synthesized
compounds. The stability of the NA-inhibitor complex was de-
Y-11, which has the lowest activity (36.60 µM) and the highest
termined based on the RMSD values of the acceptor backbone
binding energy (-13.00 kcalmol-1). Hence one can see that the
atoms (Fig. S6). On the base of MD simulations, the binding
theoretical results are consistent with the experimental results.
free energies (ΔGbind) between the 11 new inhibitors and NA
Table 3. The Calculated Binding Free Energies (ΔGbind, kcalmol-1) of Ligand-2HU0 Complexes via MM/PBSA and
MM/GBSA Methods
No.
IC50(μM)
1.92
VDW
-36.74
-38.30
-34.39
-30.57
EEL
ΔGgas
ΔGGB
31.36
26.17
27.87
40.53
ΔGSA
-4.36
-4.60
-4.09
-4.48
ΔGsolv(GB)
26.99
ΔGbind(GB)
-21.05
ΔGPB
32.67
28.60
25.45
42.28
ΔGSA ΔGsolv(PB)
ΔGbind(PB)
-18.83
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Lead *
Y-1
-11.41
-17.98
-15.54
-30.60
-48.04
-56.28
-49.93
-61.17
-3.67
-3.58
-3.37
-2.98
29.21
25.02
22.07
39.30
0.21
21.57
-34.71
-31.26
Y-2
3.71
23.78
-26.15
-27.85
Y-3
5.47
36.05
-25.12
-21.87
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Y-4
Y-5
Y-6
Y-7
Y-8
Y-9
Y-10
Y-11
3.97
-40.86
-29.53
-42.66
-35.57
-28.81
-27.12
-29.56
-21.01
-23.47
-55.04
-8.16
-64.33
-84.57
-50.82
-73.05
-68.23
-33.21
-54.58
-26.32
44.33
68.21
27.72
49.70
52.79
18.32
37.69
15.57
-5.16
-4.24
-5.33
-4.60
-4.07
-3.05
-3.70
-2.39
39.80
63.97
22.38
45.09
48.72
15.27
34.00
13.18
-24.52
-20.60
-28.44
-26.96
-19.51
-17.94
-20.58
-13.14
49.95
68.09
31.54
55.88
54.67
18.00
41.13
15.45
-4.03
-3.01
-4.03
-3.23
-3.27
-2.66
-2.90
-2.13
45.91
65.08
27.52
52.64
51.39
15.35
38.23
13.31
-18.41
1
2
3
4
5
6
7
8
14.83
11.64
13.77
9.67
-19.49
-23.21
-19.41
-16.84
-17.87
-16.34
-13.00
-36.48
-39.42
-6.09
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
10.56
22.74
36.60
-25.01
-5.31
*: Lead is stands for AN-329/10738021.
Thanks for financial support by Natural Science Foundation of
Shanghai (No. 15ZR1440400), Collaborative Innovation Fund
(No. XTCX2016-14), Middle and Youth Teachers Scientific and
Technological Talents Developing Fund (No. ZQ 2018-20),
Shanghai Municipal Education Commission (Plateau Discipline
Construction Program).
In this research, a novel lead NA inhibitor AN-
329/10738021 (IC50=1.92 μM) was discovered by virtual
screening, MD simulations, and bioassay validation. Structural
optimization of AN-329/10738021 leads to discovery of a series
of 11 novel inhibitors (Y-1-Y-11). These inhibitors exhibit good
inhibition activity in the range of potency of FDA-approved
oseltamivir carboxylate. They have concise chemical structures
and are relatively easy to synthesize, with good potential for fur-
ther improvement by introducing novel moieties and extension
of structures. Particularly, compound Y-1 exerts the best NA-
inhibition activity (IC50 = 0.21 µM), which is better than OSC
(IC50 = 3.04 µM). Molecular docking analysis indicates that the
good inhibition activity of Y-1 may be ascribed to the elonga-
tion of benzylidene moiety of the molecule to the 430-cavity.
430-cavity plays an important role in discovery of novel NA in-
hibitors.
Notes
The authors declare that there is no financial/commercial conflict
of interest.
ACKNOWLEDGMENT
Authors are thankful to WuXi AppTec for their help in bioassay.
ABBREVIATIONS
NA, neuraminidase; OSC, oseltamivir carboxylate; MD, molecular
dynamics; GH, Güner-Henry; RMSD, root-mean-square deviation;
MM/GBSA, Molecular Mechanics/Generalized Born Surface Area;
MM-PBSA, Molecular Mechanism/Poison-Boltzman Surface Area.
ASSOCIATED CONTENT
Supporting Information
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AUTHOR INFORMATION
Corresponding Author
*Phone: +86-21-6087-3250. Email: chengliping@sit.edu.cn
Present Addresses
School of Chemical and Environmental Engineering, Shanghai In-
stitute of Technology, Shanghai 201418, China
Author Contributions
The manuscript was finished through contributions of all authors.
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Insert Table of Contents artwork here
A series of novel neuraminidase inhibitors containing the scaffold of N’-benzylidene benzohydrazone
were designed and synthesized based on virtual screening.
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