I
nte
rna
t
io
na
l J
o
urna
l o
f
P
u
bli
c
H
ea
lt
h Science
(
I
J
P
H
S)
Vo
l.
14
,
No
.
3
,
Sep
tem
b
er
2
0
2
5
,
p
p
.
1
62
9
~
1
63
4
I
SS
N:
2252
-
8
8
0
6
,
DOI
: 1
0
.
1
1
5
9
1
/ijp
h
s
.
v
1
4
i3
.
2
6
2
0
8
1629
J
o
ur
na
l ho
m
ep
a
g
e
:
h
ttp
:
//
ijp
h
s
.
ia
esco
r
e.
co
m
G
eno
me mi
ning
o
f
seco
nda
ry
me
tabo
lites f
ro
m ma
ri
ne
Strep
to
m
yces
spp
.
as
potent
t
hera
p
e
utics f
o
r
RET
-
spe
cific
no
n
-
sm
a
ll
-
cell lung ca
ncer
Rhy
dh
y
Ra
s
ik
a
G
urm
ura
s
,
H
em
a
Na
nd
ini
Ra
j
endra
n K
rish
na
m
o
o
rt
hy
,
Ra
m
a
na
t
ha
n K
a
rupp
a
s
a
m
y
D
e
p
a
r
t
me
n
t
o
f
B
i
o
t
e
c
h
n
o
l
o
g
y
,
S
c
h
o
o
l
o
f
B
i
o
S
c
i
e
n
c
e
s
a
n
d
Te
c
h
n
o
l
o
g
y
,
V
e
l
l
o
r
e
I
n
st
i
t
u
t
e
o
f
Te
c
h
n
o
l
o
g
y
,
V
e
l
l
o
r
e
,
I
n
d
i
a
Art
icle
I
nfo
AB
S
T
RAC
T
A
r
ticle
his
to
r
y:
R
ec
eiv
ed
No
v
4
,
2
0
2
4
R
ev
is
ed
Dec
2
4
,
2
0
2
4
Acc
ep
ted
Ma
r
6
,
2
0
2
5
Th
e
re
a
rra
n
g
e
d
d
u
rin
g
tran
sfe
c
ti
o
n
(RET
)
g
e
n
e
e
n
c
o
d
e
s
a
ty
ro
si
n
e
k
in
a
se
o
n
c
o
g
e
n
e
imp
li
c
a
ted
i
n
v
a
rio
u
s
c
a
n
c
e
rs,
in
c
lu
d
in
g
n
o
n
-
sm
a
ll
-
c
e
ll
lu
n
g
c
a
n
c
e
r
(NSCL
C).
Ti
ll
n
o
w,
m
u
lt
i
p
le
k
i
n
a
se
in
h
ib
i
to
rs
a
re
c
o
m
m
o
n
ly
u
se
d
to
trea
t
RET
-
p
o
siti
v
e
NSCL
C.
Ho
we
v
e
r,
th
e
se
in
h
i
b
it
o
rs
o
ft
e
n
e
x
h
ib
it
sig
n
ifi
c
a
n
t
t
o
x
icit
y
a
n
d
d
e
m
o
n
str
a
te
re
d
u
c
e
d
e
ffica
c
y
a
n
d
s
p
e
c
ifi
c
it
y
t
o
wa
r
d
RET
.
Re
c
e
n
tl
y
,
b
io
a
c
ti
v
e
c
o
m
p
o
u
n
d
s
d
e
ri
v
e
d
fro
m
m
a
rin
e
so
u
rc
e
s
h
a
v
e
sh
o
wn
p
r
o
m
isin
g
a
n
ti
c
a
n
c
e
r
p
r
o
p
e
rti
e
s.
Th
e
re
fo
re
,
th
is
st
u
d
y
a
ime
d
t
o
id
e
n
ti
f
y
e
ffe
c
t
iv
e
b
i
o
a
c
ti
v
e
c
o
m
p
o
u
n
d
s
fro
m
m
a
rin
e
S
tre
p
to
my
c
e
s
sp
e
c
ies
u
sin
g
a
v
irt
u
a
l
sc
re
e
n
in
g
a
p
p
r
o
a
c
h
to
a
d
d
re
ss
th
e
se
li
m
it
a
ti
o
n
s.
A
li
tera
tu
re
se
a
rc
h
id
e
n
ti
fied
2
0
m
a
rin
e
S
tr
e
p
to
my
c
e
s
sp
e
c
ies
a
s
p
o
ten
ti
a
l
so
u
rc
e
s
o
f
b
io
a
c
ti
v
e
c
o
m
p
o
u
n
d
s.
T
h
e
a
n
t
i
b
io
ti
c
s
a
n
d
se
c
o
n
d
a
ry
m
e
tab
o
li
t
e
a
n
a
ly
sis
sh
e
ll
(
a
n
ti
S
M
ASH
)
o
n
li
n
e
to
o
l
we
re
u
se
d
to
a
n
a
ly
z
e
th
e
g
e
n
e
c
lu
ste
rs
o
f
th
e
se
m
a
rin
e
S
tre
p
t
o
my
c
e
s
sp
e
c
ies
,
re
v
e
a
li
n
g
7
,
2
5
1
m
e
tab
o
li
tes
.
A
to
tal
o
f
6
6
1
d
isti
n
c
t
m
e
tab
o
li
tes
we
re
a
n
a
ly
z
e
d
th
r
o
u
g
h
a
c
o
m
p
re
h
e
n
siv
e
a
rra
y
o
f
v
irt
u
a
l
sc
re
e
n
in
g
m
e
th
o
d
o
l
o
g
ies
.
Th
e
m
o
lec
u
lar
d
o
c
k
in
g
a
n
d
p
h
a
rm
a
c
o
k
in
e
ti
c
a
n
a
ly
sis
re
su
lt
e
d
in
th
e
i
d
e
n
ti
fica
ti
o
n
o
f
f
o
u
r
m
e
tab
o
li
tes
with
b
e
tt
e
r
b
in
d
in
g
sc
o
re
s
a
n
d
p
h
a
rm
a
c
o
lo
g
ica
l
p
r
o
p
e
rti
e
s
t
h
a
n
p
ra
lse
ti
n
ib
.
Co
ll
e
c
ti
v
e
ly
,
we
h
y
p
o
th
e
siz
e
th
a
t
th
e
id
e
n
ti
fied
b
i
o
a
c
ti
v
e
c
o
m
p
o
u
n
d
s
c
o
u
ld
b
e
c
o
n
si
d
e
re
d
a
s p
o
ten
t
lea
d
s fo
r
fu
rth
e
r
a
n
a
l
y
sis.
K
ey
w
o
r
d
s
:
B
io
ac
tiv
e
co
m
p
o
u
n
d
s
Do
ck
in
g
Dr
u
g
lik
elin
ess
L
u
n
g
ca
n
ce
r
S
tr
ep
to
myc
es
T
h
is i
s
a
n
o
p
e
n
a
c
c
e
ss
a
rticle
u
n
d
e
r th
e
CC B
Y
-
SA
li
c
e
n
se
.
C
o
r
r
e
s
p
o
nd
ing
A
uth
o
r
:
R
am
an
ath
an
Kar
u
p
p
asam
y
Dep
ar
tm
en
t o
f
B
io
tech
n
o
lo
g
y
,
Sch
o
o
l o
f
B
io
Scien
ce
s
an
d
T
ec
h
n
o
lo
g
y
,
Vello
r
e
I
n
s
titu
te
o
f
T
ec
h
n
o
lo
g
y
Vello
r
e,
T
am
il Na
d
u
,
I
n
d
ia
E
m
ail:
k
r
am
an
ath
a
n
@
v
it.a
c.
in
1.
I
NT
RO
D
UCT
I
O
N
T
h
e
p
r
ev
alen
ce
o
f
lu
n
g
ca
n
c
er
in
th
e
wo
r
ld
h
as
b
ee
n
est
im
ated
to
2
.
4
lak
h
ca
s
es
in
2
0
2
3
.
T
h
e
in
cid
en
ce
o
f
lu
n
g
ca
n
ce
r
in
I
n
d
ia
co
n
tin
u
es
to
g
r
o
w
ex
p
o
n
en
tially
with
ev
er
y
p
ass
in
g
y
ea
r
,
th
u
s
m
ak
in
g
it
ess
en
tial
to
d
ev
elo
p
n
ew
an
d
ef
f
ec
tiv
e
th
er
ap
eu
tics
f
o
r
its
tr
ea
tm
en
t.
No
tab
ly
,
8
5
%
o
f
lu
n
g
ca
n
ce
r
ca
s
es
ac
co
u
n
ts
f
o
r
n
o
n
-
s
m
all
ce
ll
lu
n
g
ca
n
ce
r
(
NSC
L
C
)
[
1
]
.
T
ar
g
eted
th
er
ap
ies
u
tili
zin
g
s
p
ec
if
i
c
in
h
ib
ito
r
s
ag
ain
s
t
o
n
co
g
e
n
ic
k
in
ases
h
av
e
r
ev
o
lu
tio
n
ized
th
e
tr
ea
tm
en
t
o
f
c
an
ce
r
,
in
clu
d
i
n
g
NSC
L
C
[
2
]
.
Nev
er
th
eless
,
th
e
d
ev
elo
p
m
e
n
t
o
f
ac
q
u
ir
e
d
r
esis
tan
ce
to
th
ese
th
er
ap
eu
tics
h
as
em
er
g
ed
as
a
s
u
b
s
tan
tial
o
b
s
t
ac
le
in
d
ev
elo
p
in
g
m
o
r
e
ef
f
ec
tiv
e
an
d
s
p
ec
if
ic
in
h
ib
ito
r
s
[
3
]
.
On
e
o
f
th
e
r
ec
u
r
r
e
n
t
m
u
tatio
n
s
f
o
u
n
d
in
NSC
L
C
is
R
E
T
g
en
e
f
u
s
io
n
s
ca
u
s
ed
b
y
th
e
in
te
g
r
atio
n
o
f
two
ju
x
tap
o
s
ed
g
e
n
es
th
at
wer
e
o
th
er
wis
e
f
u
n
ctio
n
in
g
i
n
d
ep
en
d
en
tly
o
f
ea
ch
o
th
er
.
R
ea
r
r
an
g
ed
d
u
r
in
g
tr
an
s
f
ec
tio
n
(
R
E
T
)
,
a
ty
r
o
s
in
e
k
in
ase
r
ec
ep
to
r
,
w
h
ich
p
lay
s
a
cr
u
cial
r
o
le
in
th
e
ce
n
tr
al
an
d
p
er
ip
h
er
al
n
er
v
o
u
s
s
y
s
tem
s
,
h
as
b
ee
n
id
e
n
tifie
d
t
o
ex
h
i
b
it
o
v
e
r
ex
p
r
ess
io
n
in
1
%
–
2
%
o
f
p
atien
ts
with
NSC
L
C
[
4
]
.
Ou
t
o
f
th
e
4
5
R
E
T
f
u
s
io
n
p
ar
tn
er
s
th
at
h
a
v
e
b
ee
n
id
en
tifi
ed
i
n
NSC
L
C
,
th
e
m
o
s
t
co
m
m
o
n
o
n
es
th
at
h
av
e
b
ee
n
s
tu
d
ied
ar
e
Evaluation Warning : The document was created with Spire.PDF for Python.
I
SS
N
:
2
2
5
2
-
8
8
0
6
I
n
t J Pu
b
lic
Hea
lth
Sci
,
Vo
l.
14
,
No
.
3
,
Sep
tem
b
er
20
25
:
1
62
9
-
1
63
4
1630
KI
F5
B
,
C
C
DC
6
,
an
d
NC
OA4
.
Mu
ltip
le
k
in
ase
in
h
ib
ito
r
s
(
MK
I
s
)
s
u
ch
as v
an
d
etan
ib
an
d
ca
b
o
za
n
tin
ib
ar
e
t
h
e
f
ir
s
t
-
lin
e
th
er
ap
e
u
tics
f
o
r
tr
e
atin
g
p
atien
ts
with
R
E
T
-
p
o
s
itiv
e
NSC
L
C
.
So
m
e
o
f
th
e
o
th
er
cla
s
s
o
f
d
r
u
g
s
in
clu
d
e
ag
er
af
en
ib
,
s
elp
er
ca
tin
ib
,
an
d
p
r
alsetin
ib
[5
]
,
[
6
]
.
No
n
eth
eless
,
th
ese
MK
I
s
ex
h
ib
ited
o
f
f
-
tar
g
et
ad
v
er
s
e
ef
f
ec
ts
an
d
lim
ited
ef
f
icac
y
[
7
]
.
T
h
e
r
ef
o
r
e,
it
is
im
p
er
ativ
e
to
d
ev
elo
p
m
o
r
e
p
o
ten
t
tar
g
eted
k
in
ase
in
h
ib
ito
r
s
,
s
p
ec
if
ically
ag
ai
n
s
t
R
E
T
to
o
v
er
co
m
e
ac
q
u
ir
e
d
r
es
is
tan
ce
.
I
n
r
ec
e
n
t
y
ea
r
s
,
m
a
r
in
e
o
r
g
a
n
is
m
s
h
av
e
e
m
er
g
ed
as
a
s
ig
n
if
ican
t
s
o
u
r
ce
o
f
ch
em
ical
ly
ac
tiv
e
m
o
lecu
les
with
b
en
e
f
icial
b
io
ac
tiv
e
p
r
o
p
er
ties
,
in
clu
d
i
n
g
a
n
tican
ce
r
ef
f
ec
ts
[
8
]
.
I
t
is
wo
r
th
m
en
tio
n
in
g
th
at
n
u
m
er
o
u
s
n
atu
r
al
co
m
p
o
u
n
d
s
o
b
tain
e
d
f
r
o
m
m
ar
in
e
s
o
u
r
ce
s
h
av
e
b
ee
n
u
s
ed
as
th
e
r
ap
eu
t
ics
to
tr
ea
t
o
v
ar
ian
ca
n
ce
r
,
m
etastatic
b
r
ea
s
t
ca
n
ce
r
,
leu
k
em
ia
an
d
s
o
f
t
tis
s
u
e
s
ar
co
m
a
[
9
]
,
[
1
0
]
.
Fo
r
in
s
tan
ce
,
Nata
r
ajan
et
a
l.
[
1
1
]
,
em
p
l
o
y
i
n
g
a
v
ir
tu
al
s
cr
ee
n
in
g
m
et
h
o
d
,
id
en
tifie
d
s
ix
co
m
p
o
u
n
d
s
d
e
r
iv
ed
f
r
o
m
m
ar
in
e
alg
ae
as
s
tr
o
n
g
in
h
ib
ito
r
s
o
f
A
k
t1
an
d
Ak
t2
i
n
o
r
al
ca
n
ce
r
.
Similar
ly
,
Alam
r
i
et
a
l.
[
1
2
]
e
m
p
lo
y
ed
a
s
tr
u
ctu
r
e
-
b
ased
v
ir
tu
al
s
cr
ee
n
in
g
ap
p
r
o
ac
h
to
id
en
tif
y
p
o
ten
t
m
ar
in
e
co
m
p
o
u
n
d
s
as
in
h
ib
ito
r
s
f
o
r
estro
g
en
r
ec
e
p
to
r
alp
h
a
(
E
R
α
)
.
T
h
e
s
tu
d
y
s
cr
ee
n
ed
4
5
0
m
ar
in
e
-
d
er
iv
ed
co
m
p
o
u
n
d
s
an
d
r
ep
o
r
ted
s
ev
en
co
m
p
o
u
n
d
s
as
p
o
ten
tial
lead
s
f
o
r
E
R
α
-
p
o
s
itiv
e
b
r
ea
s
t
ca
n
ce
r
.
Par
ticu
lar
ly
,
th
e
g
en
u
s
S
tr
ep
to
myc
es
co
n
s
titu
tes
th
e
m
o
s
t
ex
ten
s
iv
e
tax
o
n
with
in
th
e
p
h
y
lu
m
Actin
o
b
ac
ter
ia
an
d
h
o
l
d
s
p
ar
a
m
o
u
n
t
im
p
o
r
tan
ce
f
o
r
th
e
p
h
ar
m
ac
eu
tical
s
ec
to
r
[
1
3
]
.
T
h
is
g
r
am
-
p
o
s
itiv
e
b
ac
ter
ia
is
th
e
p
r
o
d
u
ce
r
o
f
ac
tiv
e
s
ec
o
n
d
ar
y
m
etab
o
lites
,
in
clu
d
in
g
an
titu
m
o
r
,
im
m
u
n
o
s
u
p
p
r
ess
iv
e
ag
e
n
ts
,
a
n
tim
alar
ial
,
an
d
an
ti
b
io
tic.
I
n
ter
esti
n
g
ly
,
S
tr
ep
to
myc
es
is
also
th
e
s
o
u
r
ce
o
f
an
tican
ce
r
an
tib
io
tics
,
in
clu
d
in
g
d
o
x
o
r
u
b
icin
,
a
n
th
r
ac
y
clin
e
,
an
d
th
e
g
ly
co
p
ep
tid
e
b
le
o
m
y
c
in
[
1
4
]
.
Vir
tu
al
s
cr
ee
n
in
g
p
lay
s
a
p
iv
o
tal
r
o
le
in
th
e
d
is
co
v
er
y
an
d
ad
v
an
ce
m
en
t
o
f
an
tica
n
ce
r
th
er
ap
eu
tics
b
y
f
ac
ilit
atin
g
th
e
ef
f
icien
t
id
e
n
tific
atio
n
o
f
p
o
te
n
tial
d
r
u
g
ca
n
d
id
ates
f
r
o
m
v
ast
ch
em
ical
lib
r
ar
ies.
Mo
r
eo
v
e
r
,
it
ac
ce
ler
ates
th
e
d
r
u
g
d
is
co
v
er
y
p
r
o
ce
s
s
,
r
ed
u
c
es
co
s
ts
,
an
d
en
h
an
ce
s
th
e
p
r
ec
is
io
n
o
f
tar
g
etin
g
s
p
ec
if
ic
ca
n
ce
r
-
r
elate
d
p
r
o
tein
s
o
r
p
at
h
way
s
[
1
5
]
.
A
p
leth
o
r
a
o
f
s
tu
d
ies
h
av
e
b
ee
n
ca
r
r
ied
o
u
t
to
s
cr
ee
n
an
ti
-
ca
n
ce
r
ag
en
ts
u
s
in
g
c
o
m
p
u
tatio
n
al
a
p
p
r
o
ac
h
es.
Fo
r
i
n
s
tan
ce
,
Patel
et
a
l.
[
1
6
]
v
ir
t
u
ally
s
cr
ee
n
e
d
Pu
b
C
h
em
d
atab
ase
to
id
en
tify
p
o
ten
tial
VE
GFR
-
2
k
in
ase
i
n
h
ib
ito
r
s
.
T
h
e
s
tu
d
i
ed
id
en
tifie
d
f
o
u
r
c
o
m
p
o
u
n
d
s
with
b
etter
b
in
d
in
g
af
f
in
ity
,
ab
s
o
r
p
tio
n
,
d
is
t
r
ib
u
ti
o
n
,
m
etab
o
lis
m
,
an
d
e
x
cr
etio
n
(
ADM
E
)
p
r
o
p
er
ties
,
an
d
s
ca
f
f
o
ld
s
im
ilar
to
AG
-
0
1
3
7
3
6
as
VE
GFR
-
2
in
h
ib
it
o
r
s
.
I
n
an
o
th
er
s
tu
d
y
,
Mu
r
al
i
an
d
Kar
u
p
p
asam
y
[
1
7
]
s
cr
ee
n
ed
1
5
7
4
n
at
u
r
al
co
m
p
o
u
n
d
s
to
id
e
n
tify
p
o
ten
t
m
I
DH2
in
h
ib
ito
r
f
o
r
th
e
m
a
n
ag
em
en
t
o
f
g
lio
m
a.
T
h
e
r
e
p
o
r
ted
s
q
u
alen
e
as
th
e
lead
m
o
lecu
le
with
h
i
g
h
b
i
n
d
in
g
af
f
in
ity
alo
n
g
s
id
e
g
o
o
d
b
r
ain
p
en
etr
atin
g
p
o
te
n
tial
f
o
r
t
h
e
m
an
ag
e
m
en
t
o
f
g
lio
m
a
in
th
e
n
ea
r
f
u
tu
r
e.
Similar
ly
,
Kr
is
h
n
am
o
o
r
t
h
y
a
n
d
Kar
u
p
p
asam
y
[
1
8
]
v
ir
tu
a
lly
s
cr
ee
n
ed
FDA
ap
p
r
o
v
ed
m
o
lec
u
les
to
id
e
n
tify
p
o
ten
tial
PD
-
L
1
in
h
ib
ito
r
f
o
r
th
e
m
an
a
g
em
en
t
o
f
tr
ip
le
-
n
eg
ativ
e
b
r
ea
s
t
ca
n
ce
r
.
T
h
ey
id
en
tifie
d
DB
0
1
2
3
8
as
p
o
ten
t
lea
d
m
o
lecu
l
e
with
b
etter
b
in
d
in
g
af
f
in
it
y
,
p
h
ar
m
ac
o
k
in
etic
p
r
o
p
er
ties
an
d
co
n
f
o
r
m
atio
n
al
s
tab
ilit
y
th
an
B
MS
-
1166.
W
ith
th
ese
co
n
ce
p
tu
al
f
r
am
ewo
r
k
s
,
th
e
cu
r
r
e
n
t
in
v
esti
g
atio
n
aim
ed
to
ascer
tain
p
o
ten
t
b
io
ac
tiv
e
co
m
p
o
u
n
d
s
f
r
o
m
m
ar
in
e
S
tr
ep
to
myc
es
b
y
a
d
o
p
tin
g
a
v
i
r
tu
a
l
s
cr
ee
n
in
g
s
tr
ateg
y
f
o
r
co
m
b
atin
g
th
e
o
n
co
g
e
n
ic
R
E
T
m
o
d
if
icatio
n
s
in
NSC
L
C
p
atien
ts
.
T
h
e
co
m
p
lete
m
etab
o
lo
m
e
o
f
2
0
m
ar
in
e
S
tr
e
p
to
myc
es
s
p
p
.
was
ex
p
lo
r
ed
a
g
ain
s
t
R
E
T
p
r
o
tein
.
I
n
ter
esti
n
g
ly
,
th
is
is
th
e
f
ir
s
t
s
tu
d
y
o
f
its
k
in
d
to
b
e
co
n
d
u
ct
ed
with
th
e
g
o
al
o
f
u
tili
zin
g
th
e
co
m
p
lete
m
etab
o
l
o
m
e.
2.
M
E
T
H
O
D
2
.
1
.
A
c
q
ui
s
i
t
i
o
n
o
f
g
e
n
o
me
s
e
q
u
en
c
es
I
n
t
h
e
c
u
r
r
e
n
t
i
n
v
e
s
t
i
g
a
t
i
o
n
,
th
e
g
e
n
o
m
i
c
s
e
q
u
e
n
c
e
s
o
f
m
a
r
i
n
e
S
t
r
e
p
t
o
m
y
ce
s
s
p
ec
i
es
w
e
r
e
p
r
o
c
u
r
e
d
f
r
o
m
t
h
e
N
a
t
i
o
n
a
l
C
e
n
t
e
r
f
o
r
B
i
o
t
e
c
h
n
o
l
o
g
y
I
n
f
o
r
m
a
t
io
n
(
N
C
B
I
)
(
h
tt
p
s
:/
/
ww
w
.
n
cb
i
.
n
l
m
.
n
i
h
.
g
o
v
/
)
,
a
c
o
m
p
r
e
h
e
n
s
i
v
e
d
a
t
a
b
as
e
t
h
a
t
p
r
o
v
i
d
e
s
a
c
c
ess
t
o
b
i
o
l
o
g
i
c
a
l s
eq
u
e
n
c
e
s
a
n
d
a
n
n
o
t
at
i
o
n
s
p
e
r
t
a
in
i
n
g
t
o
a
wi
d
e
r
a
n
g
e
o
f
t
a
x
a
[
1
9
]
.
I
n
i
ti
a
l
l
y
,
w
e
u
s
e
d
t
h
e
k
e
y
w
o
r
d
"
S
tr
e
p
t
o
m
yc
e
s
"
t
o
r
e
t
r
i
e
v
e
t
h
e
s
e
q
u
e
n
c
es
f
r
o
m
t
h
e
NC
B
I
"
G
e
n
o
m
e"
d
a
t
a
b
a
s
e
.
T
h
e
n
,
t
o
i
d
e
n
t
i
f
y
t
h
e
m
a
r
i
n
e
-
r
e
l
a
t
e
d
s
p
e
ci
es
f
r
o
m
t
h
e
a
r
r
a
y
o
f
g
e
n
o
m
e
s
,
a
n
e
x
t
e
n
s
i
v
e
l
i
t
e
r
a
t
u
r
e
s
u
r
v
e
y
w
a
s
c
o
n
d
u
c
t
e
d
.
T
h
e
s
e
a
r
c
h
y
ie
l
d
e
d
2
0
w
h
o
l
e
g
e
n
o
m
e
a
s
s
e
m
b
l
i
e
s
,
w
h
i
c
h
w
e
r
e
d
o
w
n
l
o
a
d
e
d
a
n
d
u
t
i
l
i
s
e
d
f
o
r
f
u
r
t
h
e
r
g
e
n
o
m
e
m
i
n
i
n
g
a
n
a
l
y
s
is
.
2
.
2
.
I
d
e
n
t
i
f
i
c
a
t
i
o
n
o
f
g
e
n
e
t
i
c
d
e
t
e
r
mi
n
a
n
t
s
i
n
v
o
l
v
ed
i
n
b
i
o
lo
g
i
c
a
l
a
c
t
i
v
i
t
i
es
T
h
e
a
n
t
i
b
i
o
t
i
cs
a
n
d
s
ec
o
n
d
a
r
y
m
e
t
a
b
o
l
i
t
e
a
n
a
l
y
s
i
s
s
h
e
l
l
(
a
n
tiS
M
AS
H
)
is
a
w
e
b
i
n
t
e
r
f
a
c
e
d
e
s
i
g
n
e
d
f
o
r
g
e
n
o
m
i
c
e
x
p
l
o
r
a
t
i
o
n
,
w
h
i
c
h
e
n
h
a
n
c
e
s
t
h
e
i
d
e
n
t
i
f
i
c
at
i
o
n
a
n
d
c
h
a
r
a
c
t
e
r
i
z
a
t
i
o
n
o
f
b
i
o
s
y
n
t
h
e
t
i
c
g
e
n
e
c
l
u
s
te
r
s
(
B
GC
s
)
w
i
t
h
i
n
m
i
c
r
o
b
i
a
l
o
r
g
a
n
i
s
m
s
(
h
t
t
p
s
:
/
/
a
n
t
is
m
a
s
h
.
s
e
c
o
n
d
a
r
y
m
e
t
a
b
o
l
i
t
es
.
o
r
g
)
[
2
0
]
.
T
h
e
r
e
f
o
r
e
,
t
h
i
s
s
t
u
d
y
u
t
i
l
i
z
e
d
a
n
ti
S
MA
SH
6
.
1
.
1
b
a
c
t
e
r
i
al
v
e
r
s
i
o
n
t
o
e
x
t
r
a
c
t
th
e
p
o
t
e
n
t
s
e
c
o
n
d
a
r
y
m
e
t
a
b
o
l
i
t
es
f
r
o
m
m
a
r
i
n
e
S
t
r
e
p
t
o
m
yc
e
s
s
p
p
.
I
n
i
t
ia
l
l
y
,
i
n
t
h
e
d
a
t
a
i
n
p
u
t
t
a
b
t
h
e
2
0
g
e
n
o
m
e
s
e
q
u
e
n
c
e
s
i
n
FA
S
T
A
f
o
r
m
a
t
w
as
u
p
l
o
a
d
e
d
.
T
h
e
n
,
t
h
e
d
e
t
e
ct
i
o
n
s
t
r
i
ct
n
e
s
s
w
a
s
s
e
t
t
o
"
r
el
a
x
e
d
,
”
a
n
d
t
h
e
e
x
t
r
a
f
e
a
t
u
r
es
s
u
c
h
a
s
“
K
n
o
wn
C
l
u
s
t
e
r
B
la
s
te
r
,
"
“
M
I
B
iG
C
l
u
s
t
e
r
C
o
m
p
a
r
is
o
n
,
"
“
T
FB
S
A
n
a
l
y
s
i
s
,
"
"
Ac
t
i
v
eS
i
te
F
i
n
d
e
r
,
”
a
n
d
“S
u
b
C
l
u
s
t
e
r
B
l
as
t
e
r
”
w
e
r
e
e
n
a
b
le
d
a
n
d
s
u
b
m
i
t
t
e
d
f
o
r
p
r
e
d
i
c
ti
o
n
o
f
g
e
n
e
c
l
u
s
t
e
r
s
.
Ul
t
i
m
at
e
l
y
,
a
g
r
a
p
h
i
c
a
l
o
u
t
p
u
t
d
e
p
i
c
ti
n
g
c
o
m
p
o
u
n
d
s
i
d
e
n
t
i
f
i
e
d
as
s
e
c
o
n
d
a
r
y
m
e
t
a
b
o
l
it
e
s
w
i
ll
b
e
d
i
s
p
l
a
y
e
d
.
Evaluation Warning : The document was created with Spire.PDF for Python.
I
n
t J Pu
b
lic
Hea
lth
Sci
I
SS
N:
2252
-
8
8
0
6
Gen
o
me
min
in
g
o
f seco
n
d
a
r
y
meta
b
o
lites
fr
o
m
ma
r
in
e
S
tr
ep
to
myc
es sp
p
.
a
s
…
(
R
h
yd
h
y
R
a
s
ika
Gu
r
mu
r
a
s
)
1631
2
.
3
.
B
i
nd
in
g
a
f
f
i
n
i
t
y
a
s
s
es
s
m
e
n
t
t
h
r
o
u
g
h
mo
l
e
c
ul
a
r
d
o
c
kin
g
T
o
a
s
c
e
r
t
a
i
n
t
h
e
b
i
n
d
i
n
g
a
f
f
i
n
i
t
y
b
e
t
w
e
e
n
t
h
e
p
r
o
t
e
i
n
a
n
d
l
i
g
a
n
d
m
o
l
e
c
u
l
a
r
d
o
c
k
i
n
g
a
n
a
l
y
s
i
s
w
a
s
c
a
r
r
i
e
d
o
u
t
[
2
1
]
.
T
h
e
c
r
y
s
t
a
l
s
t
r
u
c
t
u
r
e
o
f
h
u
m
a
n
R
E
T
p
r
o
t
e
i
n
w
i
t
h
P
D
B
I
D
:
2
I
V
U
w
a
s
e
x
t
r
a
c
t
e
d
f
r
o
m
t
h
e
p
r
o
t
e
i
n
d
a
t
a
b
a
n
k
(
P
D
B
)
.
T
h
e
o
b
t
a
i
n
e
d
P
D
B
f
i
l
e
w
a
s
r
e
f
i
n
e
d
a
n
d
p
r
e
-
p
r
o
c
e
s
s
e
d
u
s
i
n
g
t
h
e
A
u
t
o
D
o
c
k
t
o
o
l
s
.
F
i
r
s
t
,
t
h
e
w
o
r
k
i
n
g
d
i
r
e
c
t
o
r
y
w
a
s
s
e
t
i
n
t
h
e
p
r
e
f
e
r
e
n
c
e
o
p
t
i
o
n
i
n
A
u
t
o
D
o
c
k
.
T
h
e
n
,
t
h
e
p
r
o
t
e
i
n
P
D
B
f
i
l
e
w
a
s
l
o
a
d
e
d
,
a
n
d
t
h
e
p
r
o
p
e
r
t
i
e
s
l
i
k
e
K
o
l
l
a
m
a
n
a
n
d
G
a
s
t
e
i
g
e
r
c
h
a
r
g
e
r
s
w
e
r
e
a
d
d
e
d
t
o
e
s
t
i
m
a
t
e
t
h
e
p
a
r
t
i
a
l
c
h
a
r
g
e
s
o
n
a
t
o
m
s
w
i
t
h
i
n
p
r
o
t
e
i
n
s
[
2
1
]
.
N
e
x
t
,
w
e
a
d
d
e
d
t
h
e
p
o
l
a
r
h
y
d
r
o
g
e
n
a
t
o
m
s
u
s
i
n
g
t
h
e
e
d
i
t
o
p
t
i
o
n
.
T
h
e
A
D
4
a
t
o
m
t
y
p
e
t
h
a
t
i
s
c
r
u
c
i
a
l
i
n
c
a
l
c
u
l
a
t
i
n
g
t
h
e
i
n
t
e
r
a
c
t
i
o
n
e
n
e
r
g
i
e
s
b
e
t
w
e
e
n
p
r
o
t
e
i
n
a
n
d
l
i
g
a
n
d
w
a
s
a
l
s
o
a
s
s
i
g
n
e
d
t
h
r
o
u
g
h
t
h
e
e
d
i
t
o
p
t
i
o
n
.
F
i
n
a
l
l
y
,
t
h
e
p
r
e
p
a
r
e
d
p
r
o
t
e
i
n
f
i
l
e
w
a
s
s
a
v
e
d
i
n
t
h
e
p
r
o
t
e
i
n
d
a
t
a
b
a
n
k
,
p
a
r
t
i
a
l
c
h
a
r
g
e
(
Q
)
,
a
n
d
t
o
r
s
i
o
n
s
(
T
)
(
“
P
D
B
Q
T
”
)
f
o
r
m
a
t
f
o
r
d
o
c
k
i
n
g
.
S
i
m
i
l
a
r
l
y
,
t
h
e
3
D
c
o
n
f
o
r
m
e
r
s
o
f
t
h
e
o
b
t
a
i
n
e
d
s
e
c
o
n
d
a
r
y
m
e
t
a
b
o
l
i
t
e
s
i
n
s
t
r
u
c
t
u
r
e
d
a
t
a
f
i
l
e
(
S
D
F
)
f
o
r
m
a
t
w
e
r
e
r
e
t
r
i
e
v
e
d
f
r
o
m
t
h
e
P
u
b
c
h
e
m
d
a
t
a
b
a
s
e
.
T
h
e
O
p
e
n
B
a
b
e
l
s
o
f
t
w
a
r
e
w
a
s
e
m
p
l
o
y
e
d
t
o
c
o
n
v
e
r
t
t
h
e
S
D
F
f
i
l
e
s
i
n
t
o
P
D
B
Q
T
f
o
r
m
a
t
f
o
r
t
h
e
p
u
r
p
o
s
e
o
f
m
o
l
e
c
u
l
a
r
d
o
c
k
i
n
g
.
I
n
t
h
i
s
s
t
u
d
y
,
t
h
e
P
y
R
x
0
.
8
v
i
r
t
u
a
l
s
c
r
e
e
n
i
n
g
t
o
o
l
w
a
s
u
s
e
d
f
o
r
d
o
c
k
i
n
g
.
I
n
i
t
i
a
l
l
y
,
t
h
e
R
E
T
p
r
o
t
e
i
n
a
n
d
t
h
e
l
i
g
a
n
d
m
o
l
e
c
u
l
e
s
w
e
r
e
l
o
a
d
e
d
i
n
t
o
t
h
e
P
y
R
x
w
o
r
k
s
p
a
c
e
.
T
o
p
e
r
f
o
r
m
b
l
i
n
d
d
o
c
k
i
n
g
,
a
g
r
i
d
b
o
x
c
o
v
e
r
i
n
g
t
h
e
e
n
t
i
r
e
p
r
o
t
e
i
n
w
a
s
g
e
n
e
r
a
t
e
d
u
n
d
e
r
t
h
e
V
i
n
a
s
e
a
r
c
h
s
p
a
c
e
.
L
a
s
t
l
y
,
t
h
e
“
f
o
r
w
a
r
d
”
b
u
t
t
o
n
u
n
d
e
r
t
h
e
V
i
n
a
w
i
z
a
r
d
w
a
s
c
l
i
c
k
e
d
t
o
r
u
n
V
i
n
a
.
T
h
e
d
o
c
k
i
n
g
p
a
r
a
m
e
t
e
r
s
w
e
r
e
c
a
r
e
f
u
l
l
y
r
e
f
i
n
e
d
t
o
e
n
s
u
r
e
t
h
e
r
e
l
i
a
b
i
l
i
t
y
a
n
d
p
r
e
c
i
s
i
o
n
o
f
t
h
e
s
i
m
u
l
a
t
i
o
n
o
u
t
c
o
m
e
s
.
2
.
4
.
A
s
s
ess
i
n
g
t
h
e
dr
u
g
-
l
i
ke
p
r
o
p
e
r
t
i
e
s
o
f
t
h
e
bi
o
a
c
t
i
v
e
c
o
mp
o
u
n
ds
D
r
u
g
-
l
i
k
e
l
i
n
es
s
i
s
a
n
es
s
e
n
t
i
al
s
t
e
p
i
n
t
h
e
d
e
v
el
o
p
m
e
n
t
o
f
s
u
c
c
e
s
s
f
u
l
s
m
a
l
l
-
m
o
le
c
u
l
e
d
r
u
g
s
.
I
t
is
d
e
t
e
r
m
i
n
e
d
b
y
a
n
a
l
y
z
i
n
g
t
h
e
p
h
y
s
i
o
c
h
e
m
i
c
al
a
n
d
s
t
r
u
ct
u
r
a
l
ch
a
r
a
c
t
e
r
is
t
i
cs
o
f
t
h
e
c
o
m
p
o
u
n
d
s
t
h
a
t
ca
n
b
e
u
s
e
d
t
o
p
r
e
d
i
c
t
t
h
e
i
r
b
e
h
a
v
i
o
r
i
n
b
i
o
l
o
g
i
c
a
l
s
y
s
t
e
m
s
[
2
2
]
.
I
n
t
e
r
e
s
t
i
n
g
ly
,
c
o
m
p
u
t
a
t
i
o
n
a
l
t
e
c
h
n
i
q
u
es
a
ll
o
w
f
o
r
t
h
e
e
f
f
i
c
i
e
n
t
r
e
f
i
n
e
m
e
n
t
o
f
t
h
e
p
h
a
r
m
a
c
o
k
i
n
e
t
i
c
p
r
o
p
e
r
t
i
e
s
a
n
d
t
o
x
i
c
i
t
y
o
f
d
r
u
g
c
a
n
d
i
d
a
t
e
s
.
T
h
e
r
e
f
o
r
e
,
i
n
t
h
i
s
s
t
u
d
y
,
t
h
e
a
b
s
o
r
p
t
i
o
n
,
d
is
t
r
i
b
u
ti
o
n
,
m
e
t
a
b
o
l
i
s
m
,
a
n
d
e
x
c
r
e
ti
o
n
(
A
DM
E
)
f
e
a
t
u
r
e
s
w
e
r
e
e
v
a
l
u
a
t
e
d
u
s
i
n
g
th
e
A
D
M
E
T
l
a
b
2
.
0
(
h
t
t
p
s
:
//
a
d
m
e
t
m
es
h
.
s
c
b
d
d
.
c
o
m
/
)
t
o
e
n
s
u
r
e
t
h
e
e
f
f
i
c
a
c
y
o
f
t
h
e
s
e
c
o
n
d
a
r
y
m
e
t
a
b
o
l
i
t
es
.
T
o
c
a
l
cu
l
a
t
e
t
h
e
p
r
o
p
e
r
t
i
es
t
h
e
S
M
I
L
E
S
f
o
r
m
u
l
a
o
f
t
h
e
m
o
l
e
c
u
l
es
w
as
g
i
v
e
n
a
s
i
n
p
u
t
t
o
t
h
e
A
D
M
E
T
l
a
b
s
e
r
v
e
r
.
3.
RE
SU
L
T
S AN
D
D
I
SCU
SS
I
O
N
3
.
1
.
Seco
nd
a
ry
m
et
a
bo
lite
g
ene
clus
t
er
di
s
t
ributio
n a
m
o
ng
g
eno
m
es
A
n
t
i
SM
A
SH
6
.
1
.
1
w
a
s
u
s
e
d
in
t
h
e
s
t
u
d
y
t
o
a
s
s
es
s
t
h
e
s
e
c
o
n
d
a
r
y
m
e
t
a
b
o
l
i
te
s
s
y
n
t
h
es
i
z
e
d
b
y
b
a
c
t
e
r
i
a
.
T
h
e
s
i
g
n
i
f
i
c
a
n
t
t
y
p
e
s
o
f
g
e
n
e
c
l
u
s
t
e
r
s
i
m
p
l
i
c
at
e
d
i
n
t
h
ei
r
b
io
s
y
n
t
h
e
s
is
a
r
e
n
o
n
-
r
i
b
o
s
o
m
a
l
p
e
p
t
i
d
e
s
y
n
t
h
e
t
as
e
s
(
N
R
P
S
)
,
p
o
l
y
k
e
t
i
d
e
s
y
n
t
h
e
ta
s
es
(
P
KS
)
,
t
e
r
p
e
n
e
,
l
i
n
a
r
i
d
i
n
,
a
n
d
b
u
t
y
r
o
l
a
c
t
o
n
e
.
E
v
i
d
e
n
c
e
f
r
o
m
l
i
t
e
r
at
u
r
e
s
u
g
g
e
s
ts
t
h
a
t
NR
PS
,
PK
S
,
a
n
d
t
e
r
p
en
e
s
e
x
h
i
b
i
t
a
w
i
d
e
r
a
n
g
e
o
f
a
p
p
l
i
c
a
t
i
o
n
s
,
w
h
i
c
h
i
n
cl
u
d
e
c
l
i
n
i
c
al
l
y
r
e
l
e
v
a
n
t
m
e
t
a
b
o
l
i
t
es
f
o
r
t
h
e
t
r
e
a
t
m
e
n
t
o
f
c
a
n
c
e
r
a
n
d
m
i
c
r
o
b
i
a
l
i
n
f
ec
t
i
o
n
s
[
2
3
]
.
F
i
g
u
r
e
1
d
e
m
o
n
s
t
r
at
e
s
t
h
e
d
i
s
t
r
i
b
u
t
i
o
n
o
f
s
e
c
o
n
d
a
r
y
m
e
t
a
b
o
l
i
te
s
p
r
o
d
u
c
e
d
b
y
t
h
e
d
i
f
f
e
r
e
n
t
i
s
o
l
a
t
es
.
T
h
e
c
o
m
p
r
e
h
e
n
s
i
v
e
g
e
n
o
m
i
c
e
v
a
l
u
a
t
i
o
n
o
f
v
a
r
i
o
u
s
m
a
r
i
n
e
S
t
r
e
p
t
o
m
yc
e
s
s
p
ec
i
es
y
i
e
l
d
e
d
a
n
a
g
g
r
e
g
a
t
e
o
f
7
2
5
1
b
i
o
a
c
t
i
v
e
s
e
c
o
n
d
a
r
y
m
e
t
a
b
o
l
it
e
s
.
F
r
o
m
t
h
e
f
i
g
u
r
e
,
i
t
c
a
n
b
e
o
b
s
e
r
v
e
d
t
h
a
t
S
t
r
e
p
t
o
m
yc
e
s
s
p
.
N
A
0
2
9
5
0
(
5
2
3
c
o
m
p
o
u
n
d
s
)
p
r
o
d
u
c
e
d
t
h
e
h
i
g
h
e
s
t
n
u
m
b
e
r
o
f
m
e
t
a
b
o
l
i
t
e
s
,
f
o
l
l
o
w
e
d
b
y
S
t
r
e
p
t
o
m
y
c
es
s
p
.
S
C
S
I
O
Z
S
0
5
2
0
(
4
8
4
c
o
m
p
o
u
n
d
s
)
a
n
d
S
t
r
e
p
t
o
m
y
c
es
s
p
.
3
0
2
5
(
4
3
0
c
o
m
p
o
u
n
d
s
)
.
I
n
a
d
d
i
t
i
o
n
,
m
o
s
t
o
f
t
h
e
m
e
ta
b
o
l
i
t
es
w
e
r
e
d
o
m
i
n
at
e
d
b
y
T
1
P
KS
,
N
PR
S
,
a
n
d
t
e
r
p
e
n
e
s
,
a
s
s
h
o
w
n
i
n
F
i
g
u
r
e
2
.
O
f
t
h
e
7
2
5
1
m
e
t
a
b
o
l
i
t
e
s
,
c
o
m
p
o
u
n
d
s
w
i
t
h
i
n
c
o
m
p
l
e
t
e
s
tr
u
c
t
u
r
e
c
o
n
f
o
r
m
a
t
i
o
n
s
a
n
d
o
v
e
r
l
a
p
p
i
n
g
m
e
t
a
b
o
l
i
t
es
w
e
r
e
el
i
m
i
n
at
e
d
.
F
i
n
a
l
l
y
,
a
t
o
ta
l
o
f
6
6
1
d
i
s
t
i
n
c
t
a
n
d
b
i
o
a
c
t
i
v
e
m
e
t
a
b
o
l
i
t
es
w
er
e
c
o
n
s
i
d
e
r
e
d
.
T
h
e
s
e
w
e
r
e
u
s
e
d
f
o
r
v
i
r
t
u
a
l
s
c
r
e
e
n
i
n
g
p
u
r
p
o
s
e
s
.
Fig
u
r
e
1
.
Dis
tr
ib
u
tio
n
o
f
s
ec
o
n
d
ar
y
m
etab
o
lites
ac
r
o
s
s
id
en
tifie
d
is
o
lates
Fig
u
r
e
2
.
C
lass
if
icatio
n
o
f
b
io
ac
tiv
e
co
m
p
o
u
n
d
s
in
to
d
if
f
er
en
t
b
io
s
y
n
th
etic
g
e
n
e
clu
s
ter
ty
p
e
Evaluation Warning : The document was created with Spire.PDF for Python.
I
SS
N
:
2
2
5
2
-
8
8
0
6
I
n
t J Pu
b
lic
Hea
lth
Sci
,
Vo
l.
14
,
No
.
3
,
Sep
tem
b
er
20
25
:
1
62
9
-
1
63
4
1632
3
.
2
.
M
o
lecula
r
do
ck
ing
a
g
a
i
ns
t
RE
T
pro
t
ein
T
o
g
ain
a
b
etter
u
n
d
er
s
tan
d
in
g
o
f
th
e
p
r
o
tein
-
lig
a
n
d
b
i
n
d
in
g
in
ter
ac
tio
n
s
,
m
o
lecu
la
r
d
o
ck
in
g
an
aly
s
is
was
p
er
f
o
r
m
ed
[
2
4
]
.
I
n
th
e
p
r
esen
t
s
tu
d
y
,
th
e
p
r
e
d
i
cted
ar
r
ay
o
f
s
ec
o
n
d
ar
y
m
etab
o
lites
alo
n
g
s
id
e
th
e
r
ef
er
en
ce
co
m
p
o
u
n
d
(
p
r
alsetin
ib
)
was
p
r
e
p
r
o
ce
s
s
ed
a
n
d
s
u
b
j
ec
ted
to
d
o
ck
i
n
g
a
n
aly
s
is
v
ia
Py
R
x
0
.
8
s
o
f
twar
e.
T
h
e
b
in
d
in
g
af
f
i
n
ity
s
co
r
e
ca
lcu
lated
th
r
o
u
g
h
th
e
Py
R
x
al
g
o
r
ith
m
p
r
o
v
ed
to
b
e
e
f
f
ec
tiv
e
in
d
if
f
er
e
n
tiatin
g
b
etwe
en
b
in
d
er
s
an
d
n
o
n
-
b
i
n
d
er
s
[
2
5
]
.
B
in
d
in
g
af
f
in
itie
s
ex
h
ib
itin
g
a
h
i
g
h
er
n
eg
ati
v
e
v
alu
e
(
k
ca
l/m
o
l)
s
ig
n
if
y
an
en
h
an
ce
d
af
f
in
it
y
f
o
r
th
e
tar
g
et
p
r
o
tein
[
2
6
]
.
T
h
e
f
in
d
in
g
s
s
h
o
wed
th
at
3
6
6
m
o
l
ec
u
les
with
b
in
d
in
g
en
er
g
ies
r
an
g
i
n
g
f
r
o
m
-
1
6
.
1
k
ca
l/m
o
l
to
-
7
.
8
k
ca
l/m
o
l
h
ad
a
h
ig
h
er
b
in
d
i
n
g
af
f
in
ity
th
a
n
p
r
alsetin
ib
(
-
7
.
7
9
k
ca
l/m
o
l)
.
T
h
u
s
,
th
ese
p
o
ten
t
m
o
lecu
les
wer
e
f
u
r
th
er
co
n
s
i
d
er
ed
f
o
r
p
h
ar
m
ac
o
k
in
etic
an
d
to
x
icity
an
aly
s
is
.
T
ab
le
1
r
e
p
r
esen
ts
th
e
d
o
c
k
in
g
s
co
r
es o
f
th
e
to
p
ten
lead
m
o
l
ec
u
les.
T
h
e
d
o
ck
ed
p
o
s
e
an
d
th
e
4
in
ter
ac
tin
g
r
esid
u
es
b
etwe
en
th
e
p
r
o
tein
an
d
lig
a
n
d
m
o
lecu
les
ar
e
d
ep
icted
in
Fig
u
r
e
3
.
Fro
m
Fig
u
r
e
3
it
ca
n
b
e
s
ee
n
th
at
all
f
o
u
r
lead
m
o
lecu
les
in
ter
ac
ted
in
th
e
s
am
e
r
eg
io
n
with
th
e
R
E
T
p
r
o
tein
.
C
o
lle
ctiv
ely
,
th
e
f
in
d
in
g
s
s
u
g
g
est
th
at
th
ese
co
m
p
o
u
n
d
s
m
a
y
s
er
v
e
as
p
r
o
m
is
in
g
in
h
ib
ito
r
s
tar
g
etin
g
th
e
R
E
T
p
r
o
tein
.
3
.
3
.
Drug
li
k
e
pro
pert
ies o
f
t
he
lea
d m
o
lecules
Ass
es
s
in
g
th
e
ADM
E
p
r
o
f
ile
o
f
th
e
lead
m
o
lecu
les
is
cr
u
cia
l
in
u
n
d
e
r
s
tan
d
in
g
t
h
eir
p
h
a
r
m
ac
o
lo
g
ical
ef
f
ec
t
[
1
8
]
.
W
e
u
s
ed
th
e
AD
ME
T
lab
web
in
ter
f
ac
e
to
an
a
ly
ze
th
e
p
h
ar
m
ac
o
k
in
etic
an
d
to
x
icity
p
r
o
p
er
ties
o
f
th
e
lead
m
o
lecu
les
in
th
is
s
tu
d
y
.
T
h
e
f
in
d
i
n
g
s
ar
e
tab
u
late
d
in
T
ab
le
2
.
I
t
is
ev
id
en
t
f
r
o
m
th
e
f
in
d
in
g
s
th
at
o
n
ly
f
o
u
r
c
o
m
p
o
u
n
d
s
,
n
am
el
y
,
s
em
iv
io
x
a
n
th
in
,
en
d
o
p
h
e
n
az
in
e
B
,
p
h
en
y
l
n
an
n
o
lo
n
e
A,
a
n
d
p
h
en
y
ln
a
n
n
o
l
o
n
e
B
,
s
atis
f
ied
th
e
p
h
ar
m
ac
o
k
in
et
ic
p
r
o
p
e
r
ties
.
Acc
o
r
d
in
g
to
th
e
r
esu
lts
,
all
f
o
u
r
lea
d
m
o
lecu
les
h
a
d
lo
g
p
-
v
alu
es
in
t
h
e
r
a
n
g
e
o
f
3
to
5
.
Similar
ly
,
p
lasma
clea
r
an
ce
,
an
im
p
o
r
t
an
t
p
h
a
r
m
ac
o
k
in
etic
p
a
r
am
et
er
,
was
also
ass
ess
ed
,
an
d
a
ll
f
o
u
r
co
m
p
o
u
n
d
s
s
h
o
wed
b
etter
clea
r
an
ce
t
h
an
t
h
e
r
ef
er
e
n
ce
.
Mo
r
e
im
p
o
r
ta
n
tly
,
th
ey
all
ex
h
ib
ited
lo
wer
m
o
lecu
lar
weig
h
t
th
an
p
r
alsetin
ib
.
Ov
er
all,
th
e
f
in
d
i
n
g
s
d
em
o
n
s
tr
ate
th
at
th
e
co
m
p
o
u
n
d
s
s
atis
f
y
L
ip
in
s
k
i
r
u
le
o
f
f
iv
e
an
d
co
u
ld
b
e
p
o
ten
t in
h
i
b
ito
r
s
o
f
th
e
R
E
T
p
r
o
tein
.
T
ab
le
2
.
ADM
E
p
r
o
p
er
ties
o
f
th
e
lead
m
o
lecu
les
S
.
N
o
C
o
m
p
o
u
n
d
n
a
m
e
M
o
l
.
w
t
(
<
5
0
0
D
a
)
n
H
A
n
H
D
Lo
g
P
(3
-
5)
C
l
e
a
r
a
n
c
e
(
>
5
)
B
B
B
(
+
v
e
)
C
Y
P
A
3
4
&
C
Y
P
D
2
6
i
n
h
i
b
i
t
o
r
1
P
r
a
l
se
t
i
n
i
b
5
3
3
.
2
7
0
11
3
3
.
0
0
6
2
.
9
8
1
Y
e
s
No
2
S
e
mi
v
i
o
x
a
n
t
h
i
n
2
7
4
.
0
8
0
5
2
3
.
8
8
4
1
2
.
0
9
5
Y
e
s
No
3
En
d
o
p
h
e
n
a
z
i
n
e
B
3
2
2
.
1
3
0
5
1
3
.
3
2
1
6
.
2
5
1
Y
e
s
No
4
P
h
e
n
y
l
n
a
n
n
o
l
o
n
e
A
2
7
8
.
1
3
0
2
0
4
.
1
1
4
8
.
5
8
8
Y
e
s
No
5
P
h
e
n
y
l
n
a
n
n
o
l
o
n
e
B
2
6
4
.
1
2
0
2
0
3
.
4
0
1
5
.
1
0
4
Y
e
s
No
(
a
)
(
b
)
(
c
)
(
d
)
(
e
)
Fig
u
r
e
3
.
I
n
ter
ac
tin
g
r
esid
u
es
b
etwe
en
R
E
T
p
r
o
tein
a
n
d
th
e
lead
m
o
lecu
les
:
(
a)
s
em
iv
io
x
an
th
in
,
(
b
)
en
d
o
p
h
en
az
in
e
B
,
(
c
)
phe
n
y
ln
an
n
o
lo
n
e
A
,
(
d
)
ph
en
y
ln
an
n
o
lo
n
e
B
,
an
d
(e
)
p
r
a
ls
etin
ib
(
r
ef
er
en
ce
)
Evaluation Warning : The document was created with Spire.PDF for Python.
I
n
t J Pu
b
lic
Hea
lth
Sci
I
SS
N:
2252
-
8
8
0
6
Gen
o
me
min
in
g
o
f seco
n
d
a
r
y
meta
b
o
lites
fr
o
m
ma
r
in
e
S
tr
ep
to
myc
es sp
p
.
a
s
…
(
R
h
yd
h
y
R
a
s
ika
Gu
r
mu
r
a
s
)
1633
T
ab
le
1
.
Do
c
k
in
g
s
co
r
e
o
f
t
o
p
ten
lead
m
o
lecu
les in
c
o
m
p
ar
i
s
o
n
with
p
r
alsetin
ib
S
.
N
o
P
u
b
C
h
e
m I
D
C
o
m
p
o
u
n
d
n
a
m
e
B
i
n
d
i
n
g
sc
o
r
e
(
k
c
a
l
/
mo
l
)
1
1
2
9
0
7
3
6
0
3
P
r
a
l
se
t
i
n
i
b
(
R
e
f
e
r
e
n
c
e
)
-
7
.
7
9
2
1
2
4
0
8
0
8
5
9
M
o
o
m
y
si
n
-
1
6
.
1
3
1
4
5
7
2
0
6
2
5
Jesse
n
i
p
e
p
t
i
n
-
1
2
.
8
4
4
4
3
5
9
0
Te
l
o
mes
t
a
t
i
n
-
1
1
.
9
5
1
6
7
9
9
3
9
7
8
H
o
r
ma
o
my
c
i
n
-
1
1
.
4
6
6
4
4
6
8
8
6
M
i
c
r
o
c
o
c
c
i
n
P
1
-
1
0
.
6
7
1
3
2
4
9
4
5
3
5
N
a
sese
a
z
i
n
e
C
-
1
0
.
5
8
1
2
5
3
4
9
C
o
r
y
n
e
b
a
c
t
i
n
-
1
0
.
5
9
2
4
8
0
0
0
D
i
n
a
c
t
i
n
-
1
0
.
3
10
2
4
9
0
0
1
7
0
X
e
n
e
m
a
t
i
d
e
-
1
0
.
1
11
5
2
8
1
3
9
4
C
h
a
r
t
r
e
u
si
n
-
1
0
.
1
4.
CO
NCLU
SI
O
N
T
h
e
cu
r
r
en
t
s
tu
d
y
f
o
cu
s
es
o
n
th
e
id
en
tific
atio
n
o
f
p
o
te
n
t
d
r
u
g
m
o
lecu
les
ag
ain
s
t
R
E
T
u
s
i
n
g
v
ir
tu
al
s
cr
ee
n
in
g
s
tr
ateg
ies.
No
tab
ly
,
th
e
s
ec
o
n
d
ar
y
m
eta
b
o
lites
f
r
o
m
m
ar
in
e
o
r
g
a
n
is
m
s
ac
t
as
p
r
o
m
is
in
g
an
ti
-
ca
n
ce
r
ag
en
ts
.
T
h
u
s
,
th
e
an
tiS
MA
SH
o
n
lin
e
p
latf
o
r
m
was
em
p
lo
y
ed
to
p
r
e
d
ict
an
d
id
en
tify
B
GC
s
f
r
o
m
m
ar
in
e
S
tr
ep
to
myc
es
,
aim
in
g
to
d
is
co
v
er
p
o
ten
t
an
ti
-
ca
n
ce
r
m
eta
b
o
lites
tar
g
etin
g
R
E
T
f
o
r
th
e
tr
e
atm
en
t
o
f
NSC
L
C
.
T
h
e
g
en
o
m
e
m
i
n
in
g
an
al
y
s
is
in
d
icate
d
th
at
m
o
s
t
m
etab
o
lites
wer
e
as
s
o
ciate
d
with
th
e
T
1
PKS,
ter
p
en
e
,
an
d
NR
PS
g
en
e
clu
s
ter
s
.
Su
b
s
eq
u
en
tly
,
th
e
m
o
lecu
lar
d
o
ck
i
n
g
an
d
p
h
ar
m
ac
o
k
in
etic
p
r
o
p
er
ty
an
aly
s
is
r
esu
lted
in
f
o
u
r
p
o
te
n
tial
co
m
p
o
u
n
d
s
ag
ain
s
t
th
e
R
E
T
p
r
o
tein
.
T
h
e
r
esu
ltan
t
lead
m
o
lecu
les
ex
h
ib
ited
b
etter
b
in
d
in
g
af
f
in
ity
an
d
a
s
atis
f
ac
to
r
y
p
h
a
r
m
ac
o
lo
g
ic
al
ac
tiv
ity
th
an
p
r
a
ls
etin
ib
.
Ov
er
all,
o
u
r
f
in
d
i
n
g
will
p
lay
a
k
ey
r
o
le
in
d
ev
elo
p
i
n
g
n
ew
p
o
ten
t m
o
l
ec
u
les f
o
r
th
e
m
an
a
g
em
en
t o
f
R
E
T
-
s
p
ec
if
ic
NSC
L
C
in
th
e
n
ea
r
f
u
tu
r
e.
W
ith
th
e
g
r
o
win
g
p
r
o
g
r
ess
in
co
m
p
u
t
atio
n
al
b
io
lo
g
y
,
s
im
ilar
r
esear
ch
u
tili
zin
g
o
th
e
r
S
tr
ep
to
m
yc
es
s
p
p
.
b
io
ac
tiv
e
co
m
p
o
u
n
d
s
ca
n
b
e
ex
p
lo
r
ed
.
Mo
r
eo
v
er
,
th
e
ac
tiv
ity
o
f
th
e
m
ar
in
e
co
m
p
o
u
n
d
s
ca
n
b
e
s
tu
d
ied
f
o
r
o
t
h
er
d
is
ea
s
e
ty
p
es in
th
e
n
ea
r
f
u
tu
r
e.
ACK
NO
WL
E
DG
E
M
E
NT
S
T
h
e
au
th
o
r
s
th
an
k
th
e
m
a
n
ag
e
m
en
t
o
f
Vello
r
e
I
n
s
titu
te
o
f
T
ec
h
n
o
lo
g
y
f
o
r
p
r
o
v
i
d
i
n
g
th
e
f
ac
ilit
ies
to
ca
r
r
y
o
u
t th
is
r
esear
ch
wo
r
k
.
RE
F
E
R
E
NC
E
S
[
1
]
Y
.
X
i
a
o
,
P
.
L
i
u
,
J.
W
e
i
,
X
.
Zh
a
n
g
,
J.
G
u
o
,
a
n
d
Y
.
Li
n
,
“
R
e
c
e
n
t
p
r
o
g
r
e
s
s
i
n
t
a
r
g
e
t
e
d
t
h
e
r
a
p
y
f
o
r
n
o
n
-
sm
a
l
l
c
e
l
l
l
u
n
g
c
a
n
c
e
r
,
”
Fro
n
t
i
e
rs
i
n
P
h
a
rm
a
c
o
l
o
g
y
,
v
o
l
.
1
4
,
F
e
b
.
2
0
2
3
,
d
o
i
:
1
0
.
3
3
8
9
/
f
p
h
a
r
.
2
0
2
3
.
1
1
2
5
5
4
7
.
[
2
]
P
.
R
a
mes
h
,
W
.
-
H
.
S
h
i
n
,
a
n
d
S
.
V
e
e
r
a
p
p
a
p
i
l
l
a
i
,
“
D
i
s
c
o
v
e
r
y
o
f
a
p
o
t
e
n
t
c
a
n
d
i
d
a
t
e
f
o
r
R
ET
-
s
p
e
c
i
f
i
c
n
o
n
-
sma
l
l
-
c
e
l
l
l
u
n
g
c
a
n
c
e
r
—
A
c
o
m
b
i
n
e
d
i
n
s
i
l
i
c
o
a
n
d
i
n
v
i
t
r
o
st
r
a
t
e
g
y
,
”
P
h
a
rm
a
c
e
u
t
i
c
s
,
v
o
l
.
1
3
,
n
o
.
1
1
,
p
.
1
7
7
5
,
O
c
t
.
2
0
2
1
,
d
o
i
:
1
0
.
3
3
9
0
/
p
h
a
r
mac
e
u
t
i
c
s1
3
1
1
1
7
7
5
.
[
3
]
M
.
A
r
a
g
h
i
e
t
a
l
.
,
“
R
e
c
e
n
t
a
d
v
a
n
c
e
s
i
n
n
o
n
-
s
ma
l
l
c
e
l
l
l
u
n
g
c
a
n
c
e
r
t
a
r
g
e
t
e
d
t
h
e
r
a
p
y
;
a
n
u
p
d
a
t
e
r
e
v
i
e
w
,
”
C
a
n
c
e
r
C
e
l
l
I
n
t
e
rn
a
t
i
o
n
a
l
,
v
o
l
.
2
3
,
n
o
.
1
,
p
.
1
6
2
,
A
u
g
.
2
0
2
3
,
d
o
i
:
1
0
.
1
1
8
6
/
s
1
2
9
3
5
-
0
2
3
-
0
2
9
9
0
-
y.
[
4
]
K
.
S
a
t
h
i
sh
k
u
mar
,
M
.
C
h
a
t
u
r
v
e
d
i
,
P
.
D
a
s,
S
.
S
t
e
p
h
e
n
,
a
n
d
P
.
M
a
t
h
u
r
,
“
C
a
n
c
e
r
i
n
c
i
d
e
n
c
e
e
st
i
ma
t
e
s
f
o
r
2
0
2
2
&
p
r
o
j
e
c
t
i
o
n
f
o
r
2
0
2
5
,
”
I
n
d
i
a
n
J
o
u
rn
a
l
o
f
Me
d
i
c
a
l
Re
s
e
a
r
c
h
,
v
o
l
.
1
5
6
,
n
o
.
4
&5
,
p
p
.
5
9
8
–
6
0
7
,
O
c
t
.
2
0
2
2
,
d
o
i
:
1
0
.
4
1
0
3
/
i
j
mr
.
i
j
mr
_
1
8
2
1
_
2
2
.
[
5
]
A
.
K
.
M
a
h
a
t
o
a
n
d
Y
.
A
.
S
i
d
o
r
o
v
a
,
“
R
ET
r
e
c
e
p
t
o
r
t
y
r
o
si
n
e
k
i
n
a
s
e
:
r
o
l
e
i
n
n
e
u
r
o
d
e
g
e
n
e
r
a
t
i
o
n
,
o
b
e
s
i
t
y
,
a
n
d
c
a
n
c
e
r
,
”
I
n
t
e
r
n
a
t
i
o
n
a
l
J
o
u
rn
a
l
o
f
M
o
l
e
c
u
l
a
r
S
c
i
e
n
c
e
s
,
v
o
l
.
2
1
,
n
o
.
1
9
,
p
.
7
1
0
8
,
S
e
p
.
2
0
2
0
,
d
o
i
:
1
0
.
3
3
9
0
/
i
j
ms
2
1
1
9
7
1
0
8
.
[
6
]
A
.
T.
R
e
g
u
a
,
M
.
N
a
j
j
a
r
,
a
n
d
H
.
-
W
.
Lo
,
“
R
ET
si
g
n
a
l
i
n
g
p
a
t
h
w
a
y
a
n
d
R
E
T
i
n
h
i
b
i
t
o
r
s
i
n
h
u
ma
n
c
a
n
c
e
r
,
”
Fr
o
n
t
i
e
rs
i
n
O
n
c
o
l
o
g
y
,
v
o
l
.
1
2
,
p
.
9
3
2
3
5
3
,
J
u
l
.
2
0
2
2
,
d
o
i
:
1
0
.
3
3
8
9
/
f
o
n
c
.
2
0
2
2
.
9
3
2
3
5
3
.
[
7
]
C
.
L
u
a
n
d
Q
.
Zh
o
u
,
“
D
i
a
g
n
o
s
t
i
c
s,
t
h
e
r
a
p
e
u
t
i
c
s
a
n
d
R
E
T
i
n
h
i
b
i
t
o
r
r
e
si
s
t
a
n
c
e
f
o
r
R
ET
f
u
si
o
n
–
p
o
si
t
i
v
e
n
o
n
-
sm
a
l
l
c
e
l
l
l
u
n
g
c
a
n
c
e
r
s
a
n
d
f
u
t
u
r
e
p
e
r
s
p
e
c
t
i
v
e
s,”
C
a
n
c
e
r
T
re
a
t
m
e
n
t
R
e
v
i
e
w
s
,
v
o
l
.
9
6
,
p
.
1
0
2
1
5
3
,
M
a
y
2
0
2
1
,
d
o
i
:
1
0
.
1
0
1
6
/
j
.
c
t
r
v
.
2
0
2
1
.
1
0
2
1
5
3
.
[
8
]
A
.
C
.
S
.
V
e
r
í
ssi
m
o
,
M
.
P
a
c
h
e
c
o
,
A
.
M
.
S
.
S
i
l
v
a
,
a
n
d
D
.
C
.
G
.
A
.
P
i
n
t
o
,
“
S
e
c
o
n
d
a
r
y
me
t
a
b
o
l
i
t
e
s
f
r
o
m
mar
i
n
e
so
u
r
c
e
s
w
i
t
h
p
o
t
e
n
t
i
a
l
u
s
e
a
s
l
e
a
d
s
f
o
r
a
n
t
i
c
a
n
c
e
r
a
p
p
l
i
c
a
t
i
o
n
s,”
Mo
l
e
c
u
l
e
s
,
v
o
l
.
2
6
,
n
o
.
1
4
,
p
.
4
2
9
2
,
Ju
l
.
2
0
2
1
,
d
o
i
:
1
0
.
3
3
9
0
/
m
o
l
e
c
u
l
e
s
2
6
1
4
4
2
9
2
.
[
9
]
D
.
S
.
W
i
s
h
a
r
t
e
t
a
l
.
,
“
D
r
u
g
B
a
n
k
:
A
k
n
o
w
l
e
d
g
e
b
a
se
f
o
r
d
r
u
g
s,
d
r
u
g
a
c
t
i
o
n
s
a
n
d
d
r
u
g
t
a
r
g
e
t
s
,
”
N
u
c
l
e
i
c
A
c
i
d
s
Re
se
a
rc
h
,
v
o
l
.
3
6
,
n
o
.
s
u
p
p
l
_
1
,
p
p
.
D
9
0
1
–
D
9
0
6
,
Ja
n
.
2
0
0
8
,
d
o
i
:
1
0
.
1
0
9
3
/
n
a
r
/
g
k
m
9
5
8
.
[
1
0
]
S
.
A
.
D
y
sh
l
o
v
o
y
a
n
d
F
.
H
o
n
e
c
k
e
r
,
“
M
a
r
i
n
e
c
o
m
p
o
u
n
d
s
a
n
d
c
a
n
c
e
r
:
u
p
d
a
t
e
s
2
0
2
0
,
”
M
a
ri
n
e
D
r
u
g
s
,
v
o
l
.
1
8
,
n
o
.
1
2
,
p
.
6
4
3
,
D
e
c
.
2
0
2
0
,
d
o
i
:
1
0
.
3
3
9
0
/
m
d
1
8
1
2
0
6
4
3
.
[
1
1
]
P
.
M
.
N
a
t
a
r
a
j
a
n
,
V
.
R
.
U
ma
p
a
t
h
y
,
A
.
M
u
r
a
l
i
,
a
n
d
B
.
S
w
a
m
i
k
a
n
n
u
,
“
C
o
mp
u
t
a
t
i
o
n
a
l
s
i
mu
l
a
t
i
o
n
s
o
f
i
d
e
n
t
i
f
i
e
d
mari
n
e
-
d
e
r
i
v
e
d
n
a
t
u
r
a
l
b
i
o
a
c
t
i
v
e
c
o
mp
o
u
n
d
s
a
s
p
o
t
e
n
t
i
a
l
i
n
h
i
b
i
t
o
r
s
o
f
o
r
a
l
c
a
n
c
e
r
,
”
Fu
t
u
r
e
S
c
i
e
n
c
e
O
A
,
v
o
l
.
8
,
n
o
.
3
,
M
a
r
.
2
0
2
2
,
d
o
i
:
1
0
.
2
1
4
4
/
f
so
a
-
2
0
2
1
-
0
1
4
8
.
[
1
2
]
A
.
A
l
a
mr
i
e
t
a
l
.
,
“
I
n
si
l
i
c
o
s
c
r
e
e
n
i
n
g
o
f
mari
n
e
c
o
mp
o
u
n
d
s
a
s
a
n
e
mer
g
i
n
g
a
n
d
p
r
o
m
i
si
n
g
a
p
p
r
o
a
c
h
a
g
a
i
n
st
e
st
r
o
g
e
n
r
e
c
e
p
t
o
r
a
l
p
h
a
‐
p
o
si
t
i
v
e
b
r
e
a
st
c
a
n
c
e
r
,
”
B
i
o
Me
d
Re
se
a
r
c
h
I
n
t
e
r
n
a
t
i
o
n
a
l
,
v
o
l
.
2
0
2
1
,
n
o
.
1
,
Ja
n
.
2
0
2
1
,
d
o
i
:
1
0
.
1
1
5
5
/
2
0
2
1
/
9
7
3
4
2
7
9
.
[
1
3
]
M
.
N
e
t
t
,
H
.
I
k
e
d
a
,
a
n
d
B
.
S
.
M
o
o
r
e
,
“
C
h
e
mI
n
f
o
r
m
a
b
s
t
r
a
c
t
:
G
e
n
o
mi
c
b
a
si
s
f
o
r
n
a
t
u
r
a
l
p
r
o
d
u
c
t
b
i
o
s
y
n
t
h
e
t
i
c
d
i
v
e
r
si
t
y
i
n
t
h
e
a
c
t
i
n
o
m
y
c
e
t
e
s,”
C
h
e
m
I
n
f
o
rm
,
v
o
l
.
2
6
,
n
o
.
1
1
,
p
p
.
1
3
6
2
–
1
3
8
4
,
Ja
n
.
2
0
0
9
,
d
o
i
:
1
0
.
1
0
0
2
/
c
h
i
n
.
2
0
1
0
0
3
2
6
8
.
[
1
4
]
M
.
M
.
P
.
T
a
n
g
e
r
i
n
a
e
t
a
l
.
,
“
M
e
t
a
b
o
l
o
mi
c
st
u
d
y
o
f
m
a
r
i
n
e
S
t
re
p
t
o
m
y
c
e
s
s
p
.
:
S
e
c
o
n
d
a
r
y
m
e
t
a
b
o
l
i
t
e
s a
n
d
t
h
e
p
r
o
d
u
c
t
i
o
n
o
f
p
o
t
e
n
t
i
a
l
a
n
t
i
c
a
n
c
e
r
c
o
mp
o
u
n
d
s,
”
PLO
S
O
N
E
,
v
o
l
.
1
5
,
n
o
.
1
2
,
p
.
e
0
2
4
4
3
8
5
,
D
e
c
.
2
0
2
0
,
d
o
i
:
1
0
.
1
3
7
1
/
j
o
u
r
n
a
l
.
p
o
n
e
.
0
2
4
4
3
8
5
.
[
1
5
]
S
.
G
h
a
z
y
,
L
.
O
k
t
a
y
,
a
n
d
S
.
D
u
r
d
a
g
i
,
“
A
n
o
v
e
l
a
l
g
o
r
i
t
h
m
f
o
r
t
h
e
v
i
r
t
u
a
l
s
c
r
e
e
n
i
n
g
o
f
e
x
t
e
n
s
i
v
e
sma
l
l
m
o
l
e
c
u
l
e
l
i
b
r
a
r
i
e
s
a
g
a
i
n
st
ER
C
C
1
/
X
P
F
p
r
o
t
e
i
n
-
p
r
o
t
e
i
n
i
n
t
e
r
a
c
t
i
o
n
f
o
r
t
h
e
i
d
e
n
t
i
f
i
c
a
t
i
o
n
o
f
t
h
e
r
a
p
e
u
t
i
c
r
e
s
i
st
a
n
c
e
-
b
y
p
a
ss
i
n
g
sm
a
l
l
a
n
t
i
c
a
n
c
e
r
mo
l
e
c
u
l
e
s
,
”
T
u
rk
i
sh
J
o
u
r
n
a
l
o
f
B
i
o
l
o
g
y
,
v
o
l
.
4
8
,
n
o
.
2
,
p
p
.
9
1
–
1
1
1
,
A
p
r
.
2
0
2
4
,
d
o
i
:
1
0
.
5
5
7
3
0
/
1
3
0
0
-
0
1
5
2
.
2
6
8
6
.
Evaluation Warning : The document was created with Spire.PDF for Python.
I
SS
N
:
2
2
5
2
-
8
8
0
6
I
n
t J Pu
b
lic
Hea
lth
Sci
,
Vo
l.
14
,
No
.
3
,
Sep
tem
b
er
20
25
:
1
62
9
-
1
63
4
1634
[
1
6
]
S
.
P
a
t
e
l
,
V
.
R
.
S
i
n
g
h
,
A
.
K
.
S
u
ma
n
,
S
.
Jai
n
,
a
n
d
A
.
K
.
S
e
n
,
“
V
i
r
t
u
a
l
s
c
r
e
e
n
i
n
g
,
d
o
c
k
i
n
g
,
a
n
d
d
e
si
g
n
i
n
g
o
f
N
e
w
V
EG
F
i
n
h
i
b
i
t
o
r
s
a
s
a
n
t
i
-
c
a
n
c
e
r
a
g
e
n
t
s
,
”
C
u
rre
n
t
D
ru
g
D
i
sc
o
v
e
ry
T
e
c
h
n
o
l
o
g
i
e
s
,
v
o
l
.
2
1
,
n
o
.
1
,
J
a
n
.
2
0
2
4
,
d
o
i
:
1
0
.
2
1
7
4
/
0
1
1
5
7
0
1
6
3
8
2
5
5
3
8
4
2
3
0
9
2
0
0
4
0
1
5
4
.
[
1
7
]
P
.
M
u
r
a
l
i
a
n
d
R
.
K
a
r
u
p
p
a
sam
y
,
“
E
x
p
l
o
r
a
t
i
o
n
o
f
n
a
t
u
r
a
l
p
r
o
d
u
c
t
d
a
t
a
b
a
se
f
o
r
t
h
e
i
d
e
n
t
i
f
i
c
a
t
i
o
n
o
f
p
o
t
e
n
t
i
n
h
i
b
i
t
o
r
a
g
a
i
n
st
I
D
H
2
mu
t
a
t
i
o
n
a
l
v
a
r
i
a
n
t
s
f
o
r
g
l
i
o
ma
t
h
e
r
a
p
y
,
”
J
o
u
rn
a
l
o
f
Mo
l
e
c
u
l
a
r
Mo
d
e
l
i
n
g
,
v
o
l
.
2
9
,
n
o
.
1
,
Ja
n
.
2
0
2
3
,
d
o
i
:
1
0
.
1
0
0
7
/
s0
0
8
9
4
-
022
-
0
5
4
0
9
-
z.
[
1
8
]
H
.
R
.
K
r
i
s
h
n
a
mo
o
r
t
h
y
a
n
d
R
.
K
a
r
u
p
p
a
sam
y
,
“
A
m
u
l
t
i
t
i
e
r
v
i
r
t
u
a
l
scr
e
e
n
i
n
g
o
f
a
n
t
a
g
o
n
i
s
t
s
t
a
r
g
e
t
i
n
g
P
D
-
1
/
P
D
-
L
1
i
n
t
e
r
f
a
c
e
f
o
r
t
h
e
man
a
g
e
me
n
t
o
f
t
r
i
p
l
e
-
n
e
g
a
t
i
v
e
b
r
e
a
s
t
c
a
n
c
e
r
,
”
Me
d
i
c
a
l
O
n
c
o
l
o
g
y
,
v
o
l
.
4
0
,
n
o
.
1
1
,
S
e
p
.
2
0
2
3
,
d
o
i
:
1
0
.
1
0
0
7
/
s1
2
0
3
2
-
0
2
3
-
0
2
1
8
3
-
7.
[
1
9
]
N
.
A
.
O
’
Le
a
r
y
e
t
a
l
.
,
“
Ex
p
l
o
r
i
n
g
a
n
d
r
e
t
r
i
e
v
i
n
g
s
e
q
u
e
n
c
e
a
n
d
m
e
t
a
d
a
t
a
f
o
r
sp
e
c
i
e
s
a
c
r
o
ss
t
h
e
t
r
e
e
o
f
l
i
f
e
w
i
t
h
N
C
B
I
d
a
t
a
s
e
t
s
,
”
S
c
i
e
n
t
i
f
i
c
D
a
t
a
,
v
o
l
.
1
1
,
n
o
.
1
,
p
.
7
3
2
,
Ju
l
.
2
0
2
4
,
d
o
i
:
1
0
.
1
0
3
8
/
s4
1
5
9
7
-
024
-
0
3
5
7
1
-
y.
[
2
0
]
K
.
B
l
i
n
e
t
a
l
.
,
“
a
n
t
i
S
M
A
S
H
7
.
0
:
n
e
w
a
n
d
i
m
p
r
o
v
e
d
p
r
e
d
i
c
t
i
o
n
s
f
o
r
d
e
t
e
c
t
i
o
n
,
r
e
g
u
l
a
t
i
o
n
,
c
h
e
m
i
c
a
l
s
t
r
u
c
t
u
r
e
s
a
n
d
v
i
s
u
a
l
i
s
a
t
i
o
n
,
”
N
u
c
l
e
i
c
Ac
i
d
s R
e
se
a
rc
h
,
v
o
l
.
5
1
,
n
o
.
W
1
,
p
p
.
W
4
6
–
W
5
0
,
Ju
l
.
2
0
2
3
,
d
o
i
:
1
0
.
1
0
9
3
/
n
a
r
/
g
k
a
d
3
4
4
.
[
2
1
]
S
.
F
o
r
l
i
,
R
.
H
u
e
y
,
M
.
E.
P
i
q
u
e
,
M
.
F
.
S
a
n
n
e
r
,
D
.
S
.
G
o
o
d
s
e
l
l
,
a
n
d
A
.
J.
O
l
s
o
n
,
“
C
o
mp
u
t
a
t
i
o
n
a
l
p
r
o
t
e
i
n
–
l
i
g
a
n
d
d
o
c
k
i
n
g
a
n
d
v
i
r
t
u
a
l
d
r
u
g
s
c
r
e
e
n
i
n
g
w
i
t
h
t
h
e
A
u
t
o
D
o
c
k
s
u
i
t
e
,
”
N
a
t
u
r
e
Pr
o
t
o
c
o
l
s
,
v
o
l
.
1
1
,
n
o
.
5
,
p
p
.
9
0
5
–
9
1
9
,
M
a
y
2
0
1
6
,
d
o
i
:
1
0
.
1
0
3
8
/
n
p
r
o
t
.
2
0
1
6
.
0
5
1
.
[
2
2
]
M
.
D
.
S
h
o
r
t
r
i
d
g
e
e
t
a
l
.
,
“
D
r
u
g
-
l
i
k
e
smal
l
m
o
l
e
c
u
l
e
s
t
h
a
t
i
n
h
i
b
i
t
e
x
p
r
e
ssi
o
n
o
f
t
h
e
o
n
c
o
g
e
n
i
c
M
i
c
r
o
R
N
A
-
2
1
,
”
A
C
S
C
h
e
m
i
c
a
l
Bi
o
l
o
g
y
,
v
o
l
.
1
8
,
n
o
.
2
,
p
p
.
2
3
7
–
2
5
0
,
F
e
b
.
2
0
2
3
,
d
o
i
:
1
0
.
1
0
2
1
/
a
c
s
c
h
e
m
b
i
o
.
2
c
0
0
5
0
2
.
[
2
3
]
M
.
S
.
M
o
h
a
n
,
S
.
A
.
S
a
l
i
m,
P
.
P
a
k
h
i
r
a
,
a
n
d
S
.
B
u
si
,
“
M
i
c
r
o
b
i
a
l
p
r
o
d
u
c
t
i
o
n
o
f
p
o
l
y
k
e
t
i
d
e
s
a
n
d
n
o
n
-
r
i
b
o
s
o
m
a
l
p
e
p
t
i
d
e
s
a
n
d
t
h
e
i
r
a
p
p
l
i
c
a
t
i
o
n
s,
”
i
n
Mi
c
ro
b
i
a
l
Pro
d
u
c
t
s
f
o
r
H
e
a
l
t
h
a
n
d
N
u
t
r
i
t
i
o
n
,
S
i
n
g
a
p
o
r
e
:
S
p
r
i
n
g
e
r
N
a
t
u
r
e
S
i
n
g
a
p
o
r
e
,
2
0
2
4
,
p
p
.
3
6
5
–
3
9
0
d
o
i
:
1
0
.
1
0
0
7
/
9
7
8
-
981
-
97
-
4
2
3
5
-
6
_
1
5
.
[
2
4
]
S
.
K
a
mr
a
n
,
A
.
S
i
n
n
i
a
h
,
M
.
A
.
M
.
A
b
d
u
l
g
h
a
n
i
,
a
n
d
M
.
A
.
A
l
sh
a
w
sh
,
“
T
h
e
r
a
p
e
u
t
i
c
p
o
t
e
n
t
i
a
l
o
f
c
e
r
t
a
i
n
t
e
r
p
e
n
o
i
d
s
a
s
a
n
t
i
c
a
n
c
e
r
a
g
e
n
t
s:
a
s
c
o
p
i
n
g
r
e
v
i
e
w
,
”
C
a
n
c
e
rs
,
v
o
l
.
1
4
,
n
o
.
5
,
p
.
1
1
0
0
,
F
e
b
.
2
0
2
2
,
d
o
i
:
1
0
.
3
3
9
0
/
c
a
n
c
e
r
s
1
4
0
5
1
1
0
0
.
[
2
5
]
S
.
D
a
l
l
a
k
y
a
n
a
n
d
A
.
J
.
O
l
so
n
,
“
S
ma
l
l
-
m
o
l
e
c
u
l
e
l
i
b
r
a
r
y
s
c
r
e
e
n
i
n
g
b
y
d
o
c
k
i
n
g
w
i
t
h
P
y
R
x
,
”
i
n
C
h
e
m
i
c
a
l
b
i
o
l
o
g
y
:
m
e
t
h
o
d
s
a
n
d
p
ro
t
o
c
o
l
s
,
N
e
w
Y
o
r
k
,
N
Y
:
S
p
r
i
n
g
e
r
,
2
0
1
5
,
p
p
.
2
4
3
–
2
5
0
.
d
o
i
:
1
0
.
1
0
0
7
/
9
7
8
-
1
-
4
9
3
9
-
2
2
6
9
-
7
_
1
9
.
[
2
6
]
S
.
S
u
b
b
u
r
a
j
,
P
.
R
a
mes
h
,
a
n
d
S
.
V
e
e
r
a
p
p
a
p
i
l
l
a
i
,
“
P
h
a
r
ma
c
o
p
h
o
r
e
-
b
a
s
e
d
h
y
p
o
t
h
e
s
i
s
c
o
mb
i
n
e
d
w
i
t
h
m
o
l
e
c
u
l
a
r
d
o
c
k
i
n
g
p
r
o
t
o
c
o
l
f
o
r
t
h
e
s
c
r
e
e
n
i
n
g
o
f
a
n
t
i
c
a
n
c
e
r
c
o
m
p
o
u
n
d
s
f
r
o
m
S
t
r
e
p
t
o
m
y
c
e
s
s
p
.
,
”
i
n
Me
t
h
o
d
s
i
n
Ac
t
i
n
o
b
a
c
t
e
r
i
o
l
o
g
y
,
2
0
2
2
,
p
p
.
3
1
9
–
3
3
3
.
d
o
i
:
1
0
.
1
0
0
7
/
9
7
8
-
1
-
0
7
1
6
-
1
7
2
8
-
1
_
4
0
.
B
I
O
G
RAP
H
I
E
S O
F
AUTH
O
RS
Rhy
d
h
y
Ra
sik
a
G
u
r
m
u
r
a
s
is
a
fin
a
l
-
y
e
a
r
Bio
tec
h
n
o
l
o
g
y
stu
d
e
n
t
a
t
VIT,
Ve
ll
o
re
,
In
d
ia,
se
t
to
g
ra
d
u
a
te
in
Au
g
u
s
t
2
0
2
5
.
Wi
th
a
str
o
n
g
fo
u
n
d
a
ti
o
n
i
n
Bio
c
h
e
m
istry
,
M
o
lec
u
lar
Bio
lo
g
y
,
a
n
d
Im
m
u
n
o
l
o
g
y
,
s
h
e
h
a
s
c
o
n
d
u
c
ted
re
se
a
rc
h
i
n
c
o
m
p
u
ta
ti
o
n
a
l
b
i
o
lo
g
y
a
n
d
m
icro
b
io
l
o
g
y
.
P
a
ss
io
n
a
te
a
b
o
u
t
c
o
m
p
u
tatio
n
a
l
d
ru
g
d
isc
o
v
e
ry
,
sh
e
a
ims
t
o
le
v
e
ra
g
e
b
io
in
f
o
rm
a
ti
c
s
a
n
d
m
a
c
h
i
n
e
lea
rn
in
g
t
o
o
ls
to
i
d
e
n
ti
f
y
a
n
d
o
p
ti
m
ize
th
e
ra
p
e
u
ti
c
c
a
n
d
id
a
tes
f
o
r
c
h
a
ll
e
n
g
in
g
d
ise
a
se
s.
S
o
o
n
,
u
n
d
e
rta
k
in
g
a
n
in
tern
sh
i
p
a
t
D
u
k
e
Un
iv
e
rsity
,
sh
e
se
e
k
s
t
o
re
fi
n
e
h
e
r
re
se
a
rc
h
sk
il
ls
a
n
d
c
o
n
tri
b
u
t
e
to
i
n
n
o
v
a
t
iv
e
a
d
v
a
n
c
e
m
e
n
ts
in
b
io
tec
h
n
o
l
o
g
y
.
S
h
e
c
a
n
b
e
c
o
n
tac
ted
a
t
e
m
a
il
:
rh
y
d
h
y
ra
sik
a
.
g
u
rm
u
r2
0
2
1
@v
i
tstu
d
e
n
t.
a
c
.
in
.
H
e
m
a
Na
n
d
i
n
i
Ra
je
n
d
r
a
n
K
r
is
h
n
a
m
o
o
r
th
y
is
a
Do
c
to
r
o
f
P
h
il
o
so
p
h
y
(
P
h
.
D.)
d
e
g
re
e
fro
m
Ve
ll
o
re
I
n
stit
u
te
o
f
T
e
c
h
n
o
l
o
g
y
(VIT),
Ve
ll
o
re
,
I
n
d
ia,
a
g
lo
b
a
ll
y
re
c
o
g
n
ize
d
i
n
stit
u
ti
o
n
k
n
o
w
n
fo
r
it
s
e
x
c
e
ll
e
n
c
e
i
n
re
se
a
rc
h
a
n
d
i
n
n
o
v
a
ti
o
n
.
S
h
e
c
a
n
b
e
c
o
n
tac
ted
a
t
e
m
a
il
:
h
e
m
a
n
a
n
d
in
i.
rk
2
0
2
0
@
v
it
st
u
d
e
n
t
.
a
c
.
in
.
Ra
m
a
n
a
th
a
n
K
a
r
u
p
p
a
sa
m
y
is
a
P
ro
fe
ss
o
r
HA
G
a
t
th
e
S
c
h
o
o
l
o
f
B
io
S
c
ien
c
e
s
a
n
d
Tec
h
n
o
l
o
g
y
,
Ve
ll
o
re
In
sti
tu
te
o
f
Tec
h
n
o
l
o
g
y
,
In
d
ia.
He
h
a
s
b
ro
a
d
in
tere
sts
in
t
h
e
a
re
a
s
o
f
b
io
i
n
fo
rm
a
ti
c
s,
p
re
c
isio
n
m
e
d
ici
n
e
,
a
n
d
b
i
g
d
a
ta
sc
ien
c
e
.
He
re
c
e
iv
e
d
th
e
p
re
sti
g
io
u
s
ICM
R
In
tern
a
ti
o
n
a
l
F
e
ll
o
ws
h
ip
a
wa
rd
fo
r
th
e
Yo
u
n
g
Bio
m
e
d
ica
l
S
c
ien
ti
st
fo
r
th
e
y
e
a
r
2
0
1
8
-
1
9
to
e
x
e
c
u
t
e
p
o
st
-
d
o
c
to
ra
l
re
se
a
rc
h
a
t
P
u
r
d
u
e
Un
iv
e
rsit
y
,
USA.
He
h
a
s
m
o
re
t
h
a
n
1
9
y
e
a
rs
o
f
re
se
a
rc
h
e
x
p
e
rien
c
e
in
Bio
in
f
o
rm
a
ti
c
s
a
n
d
h
a
s
a
u
th
o
re
d
/co
-
a
u
t
h
o
re
d
m
o
re
th
a
n
1
6
5
p
a
p
e
rs
in
t
h
e
se
a
re
a
s.
In
a
d
d
it
i
o
n
to
h
is i
n
d
e
p
e
n
d
e
n
t
re
se
a
rc
h
p
r
o
jec
ts
to
stu
d
y
d
ru
g
re
sista
n
c
e
p
a
tt
e
rn
s
in
c
a
n
c
e
r,
he
h
a
s
a
ls
o
a
c
ti
v
e
ly
c
o
ll
a
b
o
ra
ted
with
in
v
e
stig
a
to
rs
u
n
i
v
e
rsity
-
wi
d
e
,
n
a
ti
o
n
a
ll
y
,
a
n
d
in
ter
n
a
ti
o
n
a
ll
y
.
Th
e
re
se
a
rc
h
wo
rk
s
m
o
stly
f
o
c
u
se
s
o
n
m
a
c
h
in
e
lea
rn
i
n
g
m
o
d
e
l
d
e
v
e
l
o
p
m
e
n
t
f
o
r
c
a
n
c
e
r
d
ia
g
n
o
sis
a
n
d
m
a
n
a
g
e
m
e
n
t;
c
o
m
p
u
tati
o
n
a
l
d
ru
g
d
e
sig
n
a
g
a
in
st
l
u
n
g
c
a
n
c
e
r,
b
re
a
st
c
a
n
c
e
r,
in
flu
e
n
z
a
,
S
ARS
-
Co
V
-
2
,
Zi
k
a
,
a
n
d
o
t
h
e
r
d
ise
a
se
ty
p
e
s;
Im
m
u
n
o
-
i
n
fo
rm
a
ti
c
s
stra
teg
y
fo
r
v
a
c
c
in
e
d
e
v
e
l
o
p
m
e
n
t
,
a
n
d
M
o
lec
u
lar
d
y
n
a
m
ics
sim
u
latio
n
t
o
g
a
in
i
n
sig
h
t
i
n
to
t
h
e
m
e
c
h
a
n
ism
o
f
d
ru
g
re
sista
n
c
e
.
He
c
a
n
b
e
c
o
n
tac
ted
a
t
e
m
a
il
:
k
ra
m
a
n
a
th
a
n
@v
it
.
a
c
.
in
.
Evaluation Warning : The document was created with Spire.PDF for Python.