►
Description
Open project meeting for Open Source Antibiotics Series 1, the Mur Ligases.
Full Project: https://github.com/opensourceantibiotics/murligase
Relevant GitHub Issue: https://github.com/opensourceantibiotics/murligase/issues/91
On the call: Dr Edwin Tse, Yuhang Wang, Yiwei Wang (UCL), Prof Chris Dowson (chair), Dr Adrian Lloyd and Dr Laura Diaz Saez (University of Warwick), Dr Joe Eyermann, Dr Lori Ferrins (Northeastern University) (?), Bart Staker (SSGCID), Jan Abendroth (UCB Pharma).
A
Next,
absolutely
thank
you
very
much.
Okay,
so
welcome
to
open
source
antibiotics,
November
20
22,
meeting
number
91.,
we'll
start
off
on
section
one
multi-targeting
compounds
from
Warwick:
any
enemy
collection,
Adrian
Laura
over
to
you
Adrian.
Do
you
want
to
give
an
update
on
yeah.
B
Etc
additional
ice
cream
and.
C
B
These
things
yeah
yeah,
it's
good
right,
okay,
so
essentially
to
get
the
enemy
Library
going
anywhere.
We've
had
to
completely
reconfigure
the
assays
that
we
work
with,
although
we
fortunately
haven't
had
to
redesign
the
principle
of
it.
So
the
problems
that
we've
encountered
and
the
solutions
that
we've
had
to
employ
are
first
of
all,
the
implementation
of
an
efficient.
Stop.
Sorry.
D
Can
you
can
you
please
go
to
full
screen
and
get
rid
of
your
format,
so
people
can
see
the
screen
I'd
appreciate
it.
Thank
you.
B
B
D
B
So
the
first
well,
first
of
all,
was
the
party
of
an
ambition
stop
reagent.
So
at
the
moment
we
use
thermoficious
proprietary
and
Lex
registered
operations,
which
appears
to
work
very
well
in
context
of
the
10
might
be
for
assays
that
we
do.
B
The
second
problem
was
phosphate
contamination
due
to
ATP
hydrolysis
now,
because
the
acids
will
be
using
are
considerably
more
sensitive
than
the
ones
we
used
previously.
This
became
a
much
more
significant
problem
than
it
had
been
before.
So
the
resolution
was
quite
simple.
We
now
basically
have
all
our
ATP
are
quartered
out
in
one
shot:
single-use
card
Bots,
the
second
source
of
phosphate
contamination,
which
arose
from
UTP
manlac
Allah,
which
is
the
the
substrate
the
D
when
we
make
it
in-house.
B
The
enzyme
that
generates
it
directly,
which
is
Mercy,
generates
an
equivalent
amount
of
phosphates
because
the
separation
is
anion
exchange.
We
had
problems
with
variable
levels
of
phosphate,
contaminating
Utica
preparations.
B
We
also
the
other
another
problem
we
had
was
the
fact
that
heat
this
apparently
does
generate
free
radicals
on
exposure
to
light,
so
our
acid
buffer,
so
that's,
been
replaced
by
mops,
and
we
also
found
that
Murdy
itself,
although
it's
stable
at
high
concentrations,
any
cholesterol
buffer,
it
loses
activity
over
the
course
of
a
working
day.
B
B
The
resolution
again
now
we
know,
is
a
fresh
dilution
made
per
run
and
finally,
we
needed
to
improve
the
assay
window
and,
at
the
moment,
we're
using
very
low
concentrations
of
ATP.
So
we
thought
there'd
be
enough
room
to
increase
the
ATP
concentration,
which
is
the
lowest
substrate
concentration
in
there,
double
it
to
40
micro
molar
and
that
thereby
increased
window
that
we've
got
in
a
stopped
assay
and
the
result
of
all
of
that
has
been
when
I
have
a
functional,
stop
casting
so
ask
configure.
B
The
assay
is
now
nicely
linear,
with
respect
to
added
protein
in
the
top
left
hand
corner
in
the
bottom
left-hand
Corner.
The
time
course
which
shows
well-defined
activity
over
background.
The
background
in
a
stable
but
constant.
The
Z
primes
are
very
attractive
in
the
assay
at
the
moment.
Learning
at
at
least
0.6
over
the
time
course
that
we've
done
and
on
the
right
hand,
side.
B
We
basically
have
the
results
of
a
more
elaborate
Z
Prime
screen,
whereby
we
have
a
z,
Prime
of
0.79
versus
reaction
without
substrate
Z
Prime,
the
rules
that
Prime
of
0.57
versus
the
presence
of
80
PCP.
Although
if
you
take
it
to
a
background
of
ADP
CP,
that
particular
statistic
is
actually
0.7.
B
C
B
Have
data
to
report
about
the
W
compound
analogs,
but
I,
don't
have
updated
here,
although
we
will
post
it.
There
are
apparently
some
encouraging
species
in
there
which
are
providing
work
which
we'll
have
to
do
IC
equipties
with
and
that's
where
we
are
at
the
moment.
A
Great
thanks,
Adrian
for
wrestling
with
all
those
hidden
hidden
issues
that
come
to
light
when
you
go
are
as
thorough
as
you
are
in
in
teasing
them.
So
any
questions.
B
D
Originals,
okay,
so
yeah
as
just
as
a
reminder,
none
of
the
Amy
library
was,
was
ever
developed
against
pseudomonas.
It
was
against
E
coli.
So
just
just
for
the
record
here,
you
know.
None
of
the
compounds
that
were
selected
for
the
enemy
Library
were
ever
selected
against
the
pseudomonas
enzyme.
They
were
all
done
against
E
coli.
B
The
problems
with
the
assay
that
we've
had
to
overcome,
and
not
ones
that
are
specific
to
the
species
of
the
D,
so
I
am
fairly
competent,
that
this
will
actually
work
against
other
murdies
from
other
organisms,
and
also,
very
probably
other
ligas,
is
making
the
assumption
that
the
phosphate
separation
remains
as
good
as
it
is
currently
at
the
moment.
C
D
A
Yeah
I
mean
I
mean
the
first
compounds
we
run.
Joe
were
with
against
agalactic
mayor
D.
Won't
they
were.
D
And
I
think
I
shared
with
you
guys
how
the
compounds
are
selected
and
and
the
fact
that
there
was
very
little
crossover
of
the
compounds
against
some
of
the
different
isoslines
so
anyway,
that's
it.
D
A
I
mean
I
mean
the
it'll
it'll
to
run
through
the
whole
Library
it'll
probably
take
about
10
working
days.
Something
like
that.
So
you
know
it's.
It's
not
much
of
a
longer
wait
for
us
to
be
able
to
screen
a
couple
of
things.
So
I
think
the
first
thing
would
be
to
see
what
we
get
from
this
initial
screen,
how
many
of
those
match
up
against
the
agallak
ti
hits
and
and
then
we
can
get
on
to
the
E
coli
and
and
and
the
various
alternative
new
ligazers.
B
B
Shall
I
stop
sharing?
Have
we
done
that
I.
A
Great
move
on
to
number
two,
then
the
most
targeted,
elaborated
fragments
from
Diamond
fragment,
screen
lurage
onto
say
something
about
that.
F
Having
progress
on
the
epistemography,
so
I
can't
find
it
enough.
We'll
have
early
updates
on
next
month.
A
Okay,
should
we
move
on
to
number
three,
then
atomize
hits.
A
Okay,
so
we're
still
waiting
for
foreign.
B
Potential
issue
then,
like
I,
say
we
found
that
phosphate
contaminates,
the
substrates
that
we've
been
using
and
although,
in.
C
F
G
F
C
A
I'm
just
wondering
Ed
at
this
at
when,
if
we've
got
anything
to
follow
up
from
you
about
additional
suggestions
from
these
atomized
hits
or
not.
Oh.
E
Yes,
so
we
actually
just
have
a
new
Master
student
anyway
who's
going
to
be
working
on
some
chemistry
with
us,
I
guess
she
can
introduce
herself
and.
G
Another
I'm,
a
new
master
research
student
match
group,
so
I'll
be
working
on
sentence.
G
Yeah
yeah,
it
won't
be
a
school
year,
yeah.
E
A
Cool
very
good
great
anyone
else
got
any
input
on
the
atomized
hits
at
all.
I,
don't
know
whether
Matt
heard
anything
back
from
atom
wise
as
to
what
their
thoughts
were
about
their
design
and
binding.
E
A
Where
have
we
got
to
with
those?
Have
you
shipped
everything
you've
made
so
far
you
you
are.
H
Okay,
yeah
I
mean
my
kingdom
I
I
I've
I've
only
shipped
the
ac5005
and
other
relative
relevant
relevant
variants
in
the
paper,
as
well
as
the
amino
derivative
ship.
Two
only
only
that
shift
to
work,
as
for
other,
as
for
other
variants,
I'm
still
making.
A
Okay:
okay:
cool:
how
much
longer
have
you
got
Johan
with
your
your
project?.
A
Two
years,
correct,
okay,
I
think,
that's
probably
something
we
need
to
do
is
to
get
a
kind
of
a
again
chart,
together
of
all
the
different
efforts
and
who's
who's
around
for
what
period
of
time
and
actually
get
a
kind
of
a
longer
term
plan
of
progress
and
what
checkpoints
we
want
to
put
in
on
a
formal,
Gantt
chart
actually
I
think
that
would
be
I.
Think
that
would
be
handy
for
everybody.
H
Oh,
it's
about
the
synthesis.
I,
updated,
updated.
A
H
H
Products
of
these
book
protector
aims
here,
I,
say:
crew
products
not
like
just
it's,
not
something
we
back
down
after
after
reaction
is
it's
actually
instead
of
that,
it's
actually
after
purification
still
having
some
impurities
in
it,
because
the
authority
of
the
product
was
quite
similar
to
the
startup,
just
part
of
the
second
material,
some
of
the
starting
material
and
some
of
the
impurities
generated
along
the
way.
H
So
it
will
be
meaningless
to
spend
a
lot
of
time
doing
doing
the
whole
purification
just
to
get
this
so
I'm
planning
to
just
carry
on
with
recruits
product
to
to
The
Next
Step
TFA,
the
protection,
then
I
go
with
the
hdlc
electrification
to
actually
get
the
Amy
out.
That's
my
hope.
So.
A
No
okay
isn't
on
issue
at
the
moment,
so
we
can't
ask
her
to
update
on
yuan's
cat
compounds
unless
you
know
Laura,
what's
being
done
there.
F
A
H
But
I
also
ask
a
question
here:
just
about
the
I
think
we
are
we're
talking
to
that
program
to
The
Next
Step,
so
I
asked
a
question
about
the
spr
Laura
has
been,
has
updated
on
Wiki
page
I,
don't
mind.
I
can
share
the
screen.
H
Yeah
so
we're
pretty
we're
very
excited
to
see
the
cspr
results
from
Laura
several
weeks
ago.
That
was
a
it's.
H
F
Yeah
but
I
wouldn't
overestimate
that
so
I
think
that
value
is
not
true,
because
I
got
very
weak.
Abundant
you're
gonna
still
make
80s
for
any
kind
of
binding,
but
the
curves
looked
to
me
quite
weak,
so
I
think
it's
a
much
higher
value.
H
F
F
In
the
same
way
as
the
rest
for
some
reason,
so
I
get
some
binding.
Probably
is
probably
the
problems
in
the
different
structure
for
that
binding
to
happen.
Information.
Sorry
for
that
one
didn't
happen
more
efficiently
in
comparison
with
the
best.
So
it's
only
going
into
a
portion
of
the
surface
as
very
small
portion
of
the
surface
and
that's
okay.
It
is
for
that
person,
but
that
usually
means
that
binding
is
weak.
You
know
overall,
The
Binding
is
weak.
H
F
You
heard
we
got
some
activity
today.
Initial
activity
data
for
those
compounds
we've
been
trying
to
share
as
soon
as
possible
with
you.
There
are
only
a
single
ships,
experiment,
starting
one
concentration,
so
they
are
not
isolated,
but
there
is
some
kind
of
correlation
with
the
spr
essays.
So.
C
H
G
A
Oh
very
good,
it's
five,
then
nothing
else
on
acid
compounds
and
new
protein
structures.
A
Go
to
any
any
further
comment
other
than
what's
already
written
in
the
in
the
schedule
here.
A
And
just
so
yams
finished
the
ssgci
D
x-ray
collection
from
your
c.
I
Yeah
I,
don't
know
I
think
Jana's
on
his
commute
in
and
so
maybe
foreign
bicycle,
and
so
maybe,
when
he
gets
into
UCB
and
turns
his
camera
on,
he
might
want
to
say
some
final
goodbyes
I
guess
there.
I
A
A
Yeah,
okay,
take
care
of
the
turning
great
number
six.
Then
she'll
go
denevo,
computational,
modeling
Edwin
back
to
you
again.
K
Can
you
see
my
screen
yeah
yeah
I'm,
working
in
three
different
scaffolds,
but
today,
I'm
gonna
do
just
a
fast
update
in
the
first
scaffold.
The
first
derivative
is
the
time
zone
just
I'm,
just
working
the
last
step.
K
I
try
to
do
a
reaction
with
mcpba.
After
three
days,
I
got
the
diode
derivative.
I
could
see.
The
signals
like
the
lcms
signal
showed
me
like
the
mess
of
the
dial
and
also
a
bauxite
I'm
trying
to
do
the
purification
I'm
still
need
to
collect
so
analyze,
some
fractions,
not
totally
sure.
If
this
step
is
working.
K
At
the
same
time,
I
need
to
change
the
synthetic
Pathway
to
the
typhen
derivative.
I
was
trying
to
do
some
Suzuki
coupling,
but
because
I
have
a
broad
mind
and
they
start
material
here.
The
baronic
acid
I.
Have
this
broad
mind:
I
need
to
do
a
protection,
because
the
Suzuki
Optical
is
now
working.
The
Superstition
reaction
was
taking
place
and
then
I
did
the
protection.
I
have
the
moronic
acid
now
and
at
the
same
time,
I
was
work
with
the
typhen
to
get
the
the
derivative.
So
I
have
done
step
four
five.
K
Six
and
seven
I
have
now
the
carboxylic
acid
The
Next
Step
will
be
the
Suzuki
coupling
step
two
and
then
do
the
the
protection
here
to
have
the
free
of
mine
and
then
do
the
a
coupling
reaction
and
then
finally
get
the
free
online
having
the
tile
here.
The
last
step,
so
I
have
few
more
steps
to
do
it's
taking
long
way
to
do
this,
synthetic
that
this
derivative
is
more
or
less
nine
steps
now,
but
I
hope
it's
gonna
work
soon
and
now
I
guess
this
one!
G
K
If
this
is
start,
yeah
I
start
with
five
from
the
baronic
acid
I
have
like
500
milligrams,
I
start
with
five
500
milligrams,
I
have
more
or
less
300
milligrams
of
the
the
the
first
intermediate
and
down
here.
The
dial.
The
tile
fan
I
also
have
300
milligrams.
K
The
Daily
is
not
it's
good
for
these
steps,
but
the
problem
is
using
protection,
the
protection
of
I
guess
it's
increasing
the
numbers
of
steps,
but
I
took
a
look
on
other
Stark
materials.
Most
of
the
baronic
acid.
It's
expensive
and
I
tried
to
look
up
of
others
other
start
material.
But
yes,
it's
really
expensive.
This
is
the.
C
K
Way
that
I
I
find
like
I
found
like
it's,
it's
ship
and
I
can
work
with
more
steps.
But
yes,
taking
a
while
to
decide
this
compounds.
A
You
don't
have
any
more
to
update
on
soaking
and
spr
for
these
compounds
to
you.
Laura.
A
You
do
you
do,
do
you
have
any
soaking
data
or
SBR
data
that
you've
not
already
said
about
these,
you
know,
do
you
know
the
computational
compounds.
F
I
already
shared
always
be
out
right
now
for
that,
okay,
for
the
competition
compounds,
I
don't
have
more
reading
on
the
crystallography
or
I.
Don't
have
additional
data
on
this
VR,
so
this
there
is
now.
A
Yeah
so
so
Adrian
you've
screened
these
compounds
against
pseudomonas
mere
d,
and,
and
we
got
quite
a
lot
of
innovation,
of
the
coupling
enzymes,
and
so
we've
had
to
reduce
the
concentration
of
test
compounds
to
get
a
workable
assay.
So
so
I
suppose
my
question
to
Joe
and
others
is
at
what
point
do
you
start
worrying
about
intrinsic
toxicology?
If
your
compounds
at
this
stage
are
inhibiting
lots
of
coupling
enzymes.
A
Is
it
too
early
to
have
any
any
final
say
and
that
it's
worth
the
effort
to
do
the
work
around
to
reduce
screening
compound
concentrations,
even
if
they
at
this
stage
are
inhibiting
inhibiting
a
range
of
alternative
enzymes?
D
G
D
I
mean
these
are
all
small
for
I,
mean
I'm,
not
sure
which
compounds
you're
talking
about
but
I.
Think
if
you're
talking
about
the
competition
compounds,
you
talk
about
enamine
compounds
you're
talking
about
xscum
compounds,
these
are
all
fragments,
so
I
would
personally
not
be
worried
about
inhibiting
other
things
you
just
got
to
deal
with
the
logistics.
The
the
challenges
that
you're
facing
with
actually
getting
an
assay
did
you
feel
comfortable
with
right
so
but
in
terms
of
off-target
activity.
D
I
would
not
worry
about
that
at
this
point,
because
these
are
all
they're
going
to
dramatically
change,
they're
small
their
specificity.
Is
it's
not
surprising
in
my
mind
that
you
might
not
have
the
specificity?
You
would
like
against
some
other
targets,
so
in
that
sense,
I
personally,
don't
worry
about
quote
the
quote:
cytotoxic
question
you
just
asked
about
Chris,
but.
G
D
Think
it's
it's
more!
It's
more!
It's
more!
You
know
the
the
challenges
that
you
know
that
Adrian
and
his
team
is
facing
around
just
developing
assets,
they're
comfortable
with,
and
so
you
know,
and
obviously
that's
been
taking
some
effort,
real
effort
right
so.
A
D
So
I,
wouldn't
I,
wouldn't
worry
about
I,
wasn't
very
bad
I
guess
the
question
becomes
more.
Maybe
I
missed
the
point
here
of
you
know
kind
of
what
at
what
level
in
terms
of
the
the
screening
the
compounds?
What
concentrations
are
you
able
to
actually
screen
at
because
again,
the
the
challenge
here
is
these
are
fragments
so
so
in
general,
and
generally
you
wouldn't
expect
to
be
seeing.
D
B
Well
it
in
the
sort
of
in
the
presentation
I
just
gave.
We
just
use
the
model,
our
model,
inhibition,
which
is
ADP
CP
and
0.2
millimolar.
B
Typically,
when
we
do
screening
at
one
millimole,
if
we
can,
the
I'm
I'm
relatively
comfortable
with
the
fact
that
I
would,
the
expectation
would
be
I
would
have
thought
that
the
idea
of
the
issues
about
capacity
of
things
that
are
engineered
in
later
that's
correct
is.
B
With
the
atomized
liven
around
about
20
of
the
compounds
actually
did
cause
the
assay
to
fall
over
with
the
with
Becca's
enemy
screen.
It
was
something
like
about
10
to
15
percent,
as
nutrition
rate
I
think
my
gut
feeling
is,
we
probably
will
get
enough
information.
That's
useful
house
living
with
things
the
way
they
are.
We
just
have
to
be
Governor
sense
of
the
fact
that
these
things
aren't
absolutely
100
specific,
and
quite
simply,
we
probably
shouldn't
be
assuming
that
they
would
necessarily
would
be.
D
Yeah,
so
that's
that's
great
Adrian
I
mean
I.
Think
even
if
you
need
to
go
down
to
you
know,
say
500
micro
mower
in
terms
of
the
screening
concentration
for
the
for
the
library
I
think
that's
fine
I
mean
so
so,
if
you
can,
if
you
feel,
and
even
if
again
I
mean
this
is
all
we're
at
the
casino
here
right,
yeah.
C
D
At
the
casino
we've
got
600
to
spend
or
600
euros,
I
guess
the
same
with
600
pounds
now
to
spend,
and
you
know
if
we,
if,
if
we
we
come
back
and
we
end
up
getting
you
know,
we
don't
lose
all
our
money,
we
come
back
with
some
some
hits.
I.
Think
that's
great,
you
know
so
I
I
yeah
I
mean
this
is
just
and
again
the
numbers
game
and
so
I
mean
I.
Think
from
Becca's
I
got
a
rear,
D
screen
I
mean
we
actually
had.
D
You
know
a
pretty
good
hit
rate.
Actually
out
of
that
screen,
I
mean
there's
still
compounds
to
be
screened.
There
I
mean
I
know
we
we've
had
in
the
past
some
discussions
around
what
percent
of
the
vision
of
the
you
know
the
Becca
saw
you
know,
do
you
could
do
to
cut
it
off
at
25,
30
ambition
or
remaining
activity?
D
I
guess
is
the
right
word
here
or
50,
but
there
was
I
think
in
the
end
there
was
30
or
40
compounds
out
of
the
600,
so
you
know
that's
in
a
virtual
screen
for
the
most
part.
That's
that's
not
a
that's!
A
pretty
reasonable,
actually
hit
rate
so
again
if
we
got
and
whether
it's
the
pseudomonas
or
D
colign
your
D.
If
we
got
you
know,
we
get
some
30
or
40
compounds
that
that
have
some
level
of
activity
I
think
that's.
That
would
be
a
great
result.
D
So
this
sounds
sounds
good
and
again,
I
I,
just
you
know,
would
reiterate
what
Adrian
say
we
don't.
We
don't
need
to
worry
about
the
off-target
activity
right
now.
A
Yeah
I
mean
Joe,
just
came
back
to
the
previous
conversation
about
pseudomonas
versus
E
coli.
One
of
the
reasons
why
and
we've
we've
had
we've
put
in
quite
a
lot
of
effort
for
a
number
of
the
other
compound
series
on
the
pseudonymous
enzymes,
and
you
know
it
is
the
one
everyone
is
struggling
with.
A
I
know,
isn't
the
primary
design
feature,
but
if
you're
aware
of
the
organization
called
life,
Arc
they've
just
announced
a
huge
multi-multi-million
tens
of
million
pound
effort
in
a
in
a
cystic
fibrosis
Consortium
to
find
novel
inhibitors
and
that
is
being
of.
A
Right,
it's
been
announced
in
a
few
weeks
time,
and
you
know
we
think
you
know
well
and
at
the
same
time
as
a
charity,
we
we've
just
prioritized
for
antra
antibody
research
UK,
which
we've
it's
not
publicly
announced
yet
but
we're
you
know
we're
prioritizing
urinary
tract
infections
which
will
be
you
know,
E
coli.
A
Right,
yeah
we're
just
that
we
have
the
Moody
up
and
running,
and
you
know
you
know
we
don't
want
to
come
back
next
week.
Saying
we've
just
spent
a
week.
Re-Optimizing
free,
kale
I
would
probably
prefer
to
come
back
in
a
week
and
say
we
screened
half
the
library-
and
these
are.
These
are
the
hits
and.
D
Yeah
that
that's
fine
I
mean
obviously
pseudomonas
is,
you
know,
is
more
on
the
Escape.
You
know
track
and
you
know
for
cystified
fibrosis.
The
pseudomonas
is
an
important
one,
so
I
it's
just
in
the
end.
You
know
that
that's
fine!
This
is.
We
clearly
have
seen
that
certain
compounds
you
know
getting
to
pan
activity.
We
and,
as
you
get
bigger
it
becomes
harder.
You.
A
D
To
fragments
you,
you
hope
that
you
are
more,
you
know
multi-targeted
with
the
fragments,
because
they're,
small
and
they're,
not
as
you
know
as
many
interactions
that
they
have
to
optimize
to
get
activity.
So
that's
that's
fine!
It's
just
that
again.
You
know
from
the
the
original
selections
we
really
weren't
looking
at
pseudomonas,
so
that
was
my
only
concern.
A
Yeah
yeah
I
I
understand
that
Joe
we
just
we
just
thought
well,
actually
There's
an
opportunity,
and
if
we
you
know
that's,
we
had.
We
had
the
new
the
mirror
day.
You
know
at
hand
and
working
well
for
the
others.
So
we
thought
well,
let's
just
press
on
with
that.
Just
for
for
Speed,
so
we'll
will
be
onto
a
Carolina
d
as
quickly
as
we
can.
I
A
We
will
be
mercy
and
E
and
F
for
all
of
these
as
well.
So
the
part
of
the
problem
is
the
you
know
the
Matrix
that
you
look
at
once
you
once
you
start
I
I
think
we
need
probably
need
to
sit
down
and
have
a
a
thorough,
a
thorough
chat.
Once
we've
got
some
data
out
about
a
proper
screening
Cascade
as
to
how
we
optimize
that.
A
Good
thanks,
Adrian,
yeah
and
safely
in
well
done
very
good
John.
Tell
us
about
your
lovely
structure.
J
Yeah,
okay,
great
thank
you
yeah,
finally,
in
a
warmer
and
brighter
spot,
let
me
share
my
screen.
J
So
we
are
famous
for
doing
things
last
minute
and
we
did
it
again
this
time
around
these
trays
were
set
up
just
the
day
before
our
contract
ended,
I
obtained
some
Chris's
and
I
could
still
analyze
them
at
the
syncadron.
So
this
is
the
most
recent
structure
of
Muir
D
pseudomonas
mu
D
with
compound
AZ.
J
Well,
my
mouse
here
right
now,
one
three,
six,
four,
four:
nine
two
three
got
very
nice
data
set
1.85
on
stream
resolution.
You
see
the
usual
head
group
here
and
we
see
the
tail
of
the
quality
of
the
compound
quite
well
resolved.
J
J
A
copy
so
in
thicker
lines
that
is
the
tail
or
that
is
the
structure
of
chain
B
in
thinner
lines.
That's
the
tail
in
the
structure
and
chain
a
you
see
how
that
is
variable
variable
in
the
two
structures.
J
If
you
only
consider
a
the
the
pose
in
chain
B,
which
I
think
is
the
native
pose,
you
see
if
you
overlay
that
with
the
two
other
structures
we
have
determined
so
here
in
bluish
carbons,
that's
the
newest
structure,
and
then
we
have
the
other
two
structure
in
I.
Think
it's
called
coral
and
gold.
They
all
point
in
in
the
same
direction.
J
Fine,
these
structures
have
all
been
deposited
in
the
pdb.
I
have
notified
the
team
with
the
pdb
codes
and
I've
shared
all
three
structures
with
the
team
as
well.
So
that
is
my
last
contribution
here.
I
hope
this
structure
will
be
useful.
A
J
J
They
may
or
may
not
be
some
interest
in
the
company.
Traditionally
there
isn't,
a
company
is
more
interested
in
neurological
diseases.
A
A
If,
if,
if
there
is
a
a
vote
for
any,
you
know,
corporate
social
responsibility
that
won't
make
them
any
money
and-
and
they
they
were
prepared
to-
you
know-
join
this
small
Elite
group
of
you
know
Pharma
companies
that
still
have
an
interest
in
doing
this
they're
now
we'd.
Welcome
that.
J
Yeah
yeah
yeah-
that
is
definitely
awareness
in
our
company-
that
antimicrobials
are
an
important
thing,
I
mean
in
the
end.
We
have
worked
versus
gcid
for
15
years
yeah.
So
we
have
worked
a
lot
of
that.
A
Yeah
and
you
know
so
delighted,
the
other
gosh
end
of
last
week,
someone
sent
me
the
the
fact
that
GSK
have
just
terminated
their
complex.
The
urinary
trial
early
for
their
new
small
molecule
antimicrobial
I
never
knew
they
were
even
making
so
yeah.
They
they've
made
it.
D
A
That's
encouraging
for
us
in
light
of
our
previous
conversation
as
well,
and
so
yeah
I
mean
yeah
John
Ray's,
DNA
Inhibitors
are
known
for
problems
in
the
area,
but
that's
great.
It's
great.
D
D
So
obviously
I
think
based
on
Laura's
earlier
data,
these
compounds
had
no
activity
and
against
near
D.
Exactly.
J
J
That,
before
as
well
in
our
I,
think
Michael
Diaz
or
some
kind
of
binding
assays
and.
J
D
J
J
J
And
we
actually
have
that
structure
April
and
bound
to
ADP
and
bound
to
the
peptide
okay
sy9
at
7sy9
7u35.
D
So
this
brings
up
I
guess
something
I
I
just
want
to
suggest
that
we
actually
so
Bart
Bart
contacted
me,
and
you
know,
and
he's
talked
about
the
beginning
of
the
meeting-
that
ssgcid
can
continue
to
contribute
to
the
project.
So
the
question
then
becomes
you
know
what
would
be
the
best
how
to
coordinate
and
make
the
most
of
both.
You
know,
obviously
what
Laura
is
doing
and
and
what
ssgcid
is
doing
and
like
which
things
to
go,
which
things
to
go
after
so
I
suggest
I
mean
my
suggestion.
D
Is
we
maybe
have
some
separate
little
call
at
some
point
in
your
turn,
to
maybe
talk
about
what
is
the
best
way
to
use
our
our
structural
biology
resource
make
sure
we
can
do
that
here
in
the
next
five
or
ten
minutes,
but
right.
I
I
You
might
see
a
name.
You
don't
recognize
here,
Roman
Iranian,
if
you
want
to
say
hi,
Roman
Roman
does
student
at
the
University
of
Washington
and
works
for
us
and
he'll
be
helping
me
with
this
project
and
then
one
of
the
things
I
wanted
to
bring
up
that
I
emailed
I.
Think
Joe
about
was
that
yeah
we've
talked
in
the
past.
I
I
think
me
and
Matt
had
presented
on
this
project
to
niid,
and
you
know
we
we're
trying
to
look
at
different
funding
sources
that
never
quite
panned
out,
but
one
of
the
things
we
did
so
every
year
the
structural
genomic
Center
is
a
it's.
I
It's
basically
a
service
Center,
the
niaid
funds,
and
basically
they
give
us
certain
directives
on
what
we
should
work
on
and
that's
how
they
raise
funds
for
the
contract,
and
this
year
they
raised
funds
from
the
contract
from
carb
that
sort
of
just
routing
through
nid
to
to
us
to
support
antimicrobial
research
projects,
and
we
have
got
two
antimicrobial
research
projects
that
are
really
active,
and
this
is
one
of
them
and
so
I
ended
up
writing
a
proposal
to
to
niid
for
for
this
project,
but
I,
just
kind
of
you
know:
I
just
went
to
the
website
and
I
kind
of
Spun
some
things
off,
but
I
I
wanted
to
check
back
and
make
sure
we're
actually
working
on
stuff
that
you
guys
want
us
to
work
on
and
so,
and
that
also
does
include
just
making
proteins
and
which
was
one
of
the
questions
that
I
had
I.
I
F
G
A
I
think
I
think
that
would
be
good
for
us.
So
maybe
you
you
Joe
myself
and
Matt
I,
think
I
think
it
goes
hand
in
hand
with.
I
A
I
mean
it:
can
it
can
just
yes,
okay,
it
can
get
quite
large,
then,
but
I
I,
I'm
thinking
more.
You
know
strategically
around
the
screening
Cascade
as
as
well.
You
know
because
I
think,
as
we're
going
to
be
generating
hits
quite
soon,
so
I
think
we
need
to
kind
of
you
know,
make
sure
we've
got
the
E
coli
and
the
pseudomonas.
A
You
know
Crystal
systems
that
we
want
ready
to,
go
and
and
then
start
being
able
to
soak
in
hits
as
they
appear
so
I
think
it
will
be
soakable
Crystal
systems,
for
you
know,
CDE
for
E
coli
and
pseudomonas
I.
Think
that's
I,
don't
know
how
many
of
those
we
have
to
hand.
D
D
So
anyway,
that's
and
I
know
Jan
I
think
Jan
did
solve
estimated
backer
structure.
So
you
know
that's
that's
another
piece
of
structural
Equity.
We
have
in
hand
may
or
may
not
be
the
one
you
want
to
go
after,
but
I'm
saying
I.
Think
we
shouldn't
forget
about
that
as
well.
No.
A
J
I
D
And
that's
one
of
the
things
you
know
ultimately,
I
mean
one
of
the
things
that's
on
the
burner.
Now
at
some
level
is
you
know
we
we've
talked
about.
You
know
a
structural
biology
paper,
so
you
know,
there's
been
you
know,
and
so
that's
something
maybe
to
revisit
now
as
well
about
even
having
you
know
the
structures
we
have
now
and
talking.
You
know
about
having
a
paper
with
structural
biology
paper,
but
you
know
talking
about
you
know
dual
Inhibitors
so
or
dual
targeting.
Excuse
me
so
I
think
that's
that's
the
other
thing.
D
So
again,
I
think
you
know
the
when
you
said
barter
around
you
know,
part
of
the
ssgcid
mission
is
to
develop.
You
know
new
new
structural
biology
assets
and
so
I
think
you
know
if,
if
there's
an
acetobacter
license
line
that
that
makes
sense
to
kind
of
fill
in
some
kind
of
a
matrix
that
that
that
makes
sense
to
me.
A
Yeah
I
think
me
too
I
think
I.
Think
I
can't
remember
the
compound
series
now,
where
we
we,
you
saw
activity
against
c
and
e,
but
not
D.
So
you
know
we,
you
know,
tend
to
think
in
alphabetical
pairs
for
dual
Inhibitors,
but
clearly
is
an
example
where
you
can
get
in
a
CNE
inhibitor
of
an
RCN
D,
so
it
may
be
that
for
some
organism,
CE
is
the
pair.
That's
great.
F
So
I
used
to
believe
we
need
to
get
the
close
population
structures
for
this
organ,
and
maybe
that
might
be
the
reason
why
I'm
not
getting
distracted
with
the
able
crystals
and
these
inhibitors.
So
we
need
to
get
more
breathable
structures
with
either
substrates
or
products
like
a
reaction
or
something
like
that.
So
that
could
be
as
well
another
effort
we
can
make
maybe
put
a
list
of
things
that
we
that
might
be
useful
and
then
separate
them
between
the
sscc
ID
and
myself.
F
For
that
I
am
away
next
week
and
the
following
one,
but
I
can
do
meetings
the
following.
One
I
can't
do
meetings
next
week,
two.
A
A
I
mean
I
mean
I,
I
haven't
I,
don't
think
I've
shared
this,
but
we
were
lucky
enough
to
get
1.7
million
as
a
donation
from
our
next
student
that
effectively
underpins
Laura
and
Adrian
and
Julie
a
technical
posts
for
the
next
three
years.
So
that's
that's.
One
worry
off
of
my
mind
at
the
assays
and
structural
biology
posts
are
underpin.
Now
it
would
be
great
to
get
some
money
specifically
for
the
project.
But
that's
that's.
That's
a
good
start.
A
D
So
so
what
I
wasn't
quite
clear?
You
mentioned
another
series
Chris,
so
the
life
art
compounds
that
you
got
data
on
were
those
the
ones
who
are
also
causing
some
interference
or
yeah.
What's
the
stat?
What's
the
status
with
the
life
art
Equity
that
you've
received
yeah.
A
So
we've
screened
them
found
that
they
inhibited
I
think
there
was
a
couple
that
didn't
I.
Think
Anita
did
she
do
some
ic50
on
the
couple
that
didn't
I?
Don't
remember,
but
we
kind
of
stalled
that
and
pushed
on
with
the
stopped
essay
to
get
the
enemy
one.
Stranger,
okay,
okay,
all
right!
So
we
hit
we
hit
the
you
know
in
inhibition
of
coupling
enzymes
and
just
went
oh,
not
more
and
and
then
just
thought
right.
Okay,
let's
just
do
the
enemy
ones,.
A
A
All
right,
okay,
but
we'll
we'll
get
back
to
those
I
I-
have
to
make
some
decisions
about
some
of
the
additional
posts
I
have
to
I
have
to
try
and
work
out
whether
we
need
an
additional
Pair
of
Hands
on
this
project,
but
I
think
it
needs
additional
money
from
somewhere.
D
D
Chris
you're
going
to
take
the
lead
on
setting
up
crystallography.
F
A
Will
take
the
lead
in
organizing
the
meeting
with
you
me
Ian
at
least
yeah
that'd
be
great
I
mean.
Maybe
Roman
wants
to
be
involved
as
well.
Yeah,
great,
okay,
that's
great
we're
out
of
time.
The
does
I,
don't
know
how
people
fix
for
time
do.
Do
we
want
to
try
and
press
on
through
some
more
or
do
we
carry
over
till
next
time?.
A
So
we've
quickly
cut
a
quick
chat
on
the
life
Arc
Adrian
you're,
understanding
about
your
double-headed
compounds
tool
where
you've
got
two
of
those.
B
Okay
well.
Well
briefly,
there
are
a
number
of
nucleotide
analogs
which
basically
have
a
possible
digestive
bridge
in
the
middle
of
them,
and
you
have
a
nucleoside
either
side
of
that.
So,
for
example,
that
doesn't
seem
to
possible
adenosine.
B
Then
you
have,
you
can
have
a
range
of
these
things
with
a
different
lengths
of
powerful
strike
between
old
prospects
between
them.
So
it
turns
out
that
the
yielding
types
of
postmodenazine-
in
fact
the
tetroposmidenzines
full
stop-
appear
to
be
very
missionary.
Inhibitors,
relatively
speaking.
They
don't
appear
to
impact
upon
any
other
ligase
and
that's
in.
B
Because
one
well,
my
simple-minded
conception
is
that
you're
finding
something
in
The,
uridine,
Binding
pocket
or
these
enzymes
and
something
in
the
ATP
bonding
pocket
or
these
enzymes
and
the
length
of
compound
that
exists
between
these
two
bases
might
impact
the
possibility
to
bind
to
mercene
where
you'd
expect
the
distance
between
The
Binding
of
the
UDP
buyers.
Here,
the
substrate
and
The
Binding
of
atps
differ.
B
So
essentially,
that's
where
we're
at
I
was
thinking
about
screening,
the
other
commercially
available,
this
nucleosides,
so
AP,
ap2a,
ap3a,
ap5a
and
so
on.
To
see
whether
there
is
some
form
of
structurativity
relationship
going
on
and
that's
really
where
we've.
A
B
Yeah,
it
appear
to
be
quite
sharp
in
that
the
perception
of
Usman
andazine
compounds
only
and
I
mean
really
only
inhibit
vary
in
nothing
else,
so
it
then
it
might
be
that
if
I
have
a
different
length
of
between
the
two
nuclear
sides,
that
I
would
see.
Other
ligas
is
being
hit.
A
Cool
lovely.
Thank
you
very
much.
Okay,
we're
down
to
nine
and
Becca's,
not
here,
so
we
can
ignore
that
one.
Then
nine
there's
a
lot
of
mothball
actions
that
we'll
probably
need
to
do
some
admin
housekeeping
on.
A
A
Okay,
next
meeting
December
the
13th,
2
p.m,
I'm,
hoping
by
then
we'll,
hopefully
have
a
swathe
of
enamine
data.
A
A
No
good
lovely.
Thank
you
all
very
much.
Sorry
overran.
Thank
you,
Yuan
for
sorting
out
the
links
and
we'll
we'll
catch
up
soon
and
before
the
13th
Laura,
with
the
structural
biology,
stuff
and
Joe,
we
really
do
need
to
have
a
good
chat
around
screen,
Cascades
and
and
just
get
that
mapped
out
and
and
different
progression
criteria,
so
that
that
you
know
I'm
starting
to
look
at
it
now
and
thinking
we're
just
going
to
be
swamped
with
data.
So
you
know
compound
management
date.
A
A
Okay,
thank
you
all,
we'll
catch
up
soon,
all
right,
bye,.