►
Description
Open project meeting for Open Source Antibiotics Series 1, the Mur Ligases.
Full Project: https://github.com/opensourceantibiot...
Relevant GitHub Issue: https://github.com/opensourceantibiotics/murligase/issues/101
On the call: Prof. Matthew Todd, 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
Get
going
all
right,
Merl,
ligase,
open
source
antibiotics
meeting
on
Tuesday,
the
8th
of
August
welcome
everybody.
Let
me
just
share
my
screen,
so
we
know
what
we're
doing
one
second.
A
A
So
this
is
on
the
GitHub
issue.
This
is
issue
number
101,
which
is
here
and
so
yeah
I
updated
a
few
things
from
last
time,
which
I
guess
we're.
A
Gonna
talk
about
again
so
last
time,
Adrian
gave
us
an
overview
of
some
of
the
most
promising
compounds
that
were
identified
as
potential
Inhibitors
from
the
enemy
library,
and
he
was
halfway
through
looking
evaluating
the
ic50s
of
those
and
we'd
spoken
a
little
bit
about
that
and
about
some
of
the
compounds
that
have
been
shipped
to
Warwick
and
the
ongoing
cc4
car
proposal,
which
is
looking
in
great
shape.
But
mostly
it
was
about
the
evaluation
of
work
of
the
enamine
compounds.
A
So
I
guess,
if
Adrian
is
not
with
us,
then
Laura
I
was
hoping
to
start
with
you.
If
you
were
amenable
to
that
about
anything,
you've
been
doing
with
with
compounds
in
terms
of
crystallization
and
such
like.
C
Well,
Adrian
I
think
he's
he's
going
to
come
at
some
point,
so
he
should
be
able
yeah
in
terms
of
crystals
all
right.
So
we
we
I
mentioned
in
the
past
that
we
had
issues
with
the
temperature
in
the
room
of
the
crystallization
room
and
that
doesn't
agree
with
the
milagases
project
crystals.
C
So
we
we
thought
it
was
just
again
relatively
stable,
so
I
set
up
the
experiments
again
and
the
temperature
went
up
modern
sake,
six
degrees
from
what
is
supposed
to
be
so
all
the
crystals
are
gone.
Wow
yeah
is
yeah.
So
anyway,
we've
been
talking
with
the
managers
building
managers
and
things
like
that.
So
we
are
going
to
get
an
incubator,
so
we
can
get
at
least
this
project
going
because
I
can't
be
risking
it
every
time.
C
I
want
to
do
something
yeah,
so
I
couldn't
do
anything
with
the
Chris
that
I
have
set
up
and
I
haven't,
set
up
anything
until
we
had
them
the
incubator
or
until
I
know,
their
Crystal
room
is
going
to
be
stable
for
at
least
two
weeks,
so
I
put
a
temperature
Locker
as
well
in
the
room,
so
I
can
start
recording
everything
that
is
happening
during
the
day
because
we
didn't
have
any
temperature
login
either.
So
we
didn't
know
if
over
the
weekend
it
was
overheating
and
things
like
that
yeah.
C
Smoking
and
label
is
cocoa.
Stylizations
also
for
circuits
and
I
also
had
some
extra
experiments
that
I
had
done
in
to
try
to
do
some
soaking
on
crystals,
okay,
so
yeah
I
will
have
to
redo
that
at
some
point.
Okay,
all.
C
I've
got
protein,
you
know
I'm
ready
to
go,
I
just
don't
have
the
facility
at
the
moment,
I
also
tried
in
a
different
room
in
the
University.
We
have
another
crystallization
room,
but
because
of
the
changes
in
temperature
aside
again
the
room
is
not
being
stable.
So
so
the
crystals
can
grow
at
different
temperatures.
The
problem
is
that
they
have
to
say
at
that
temperature.
If
not,
the
crystals
suffer.
A
Right,
yeah,
okay,
yeah,
that
must
be
really
distressing
for
you.
A
Yeah
so
for
I
mean
obviously
the
crystallization
things
are
the
most
important
for
any
other
evaluation
of
the
of
the
compounds
like
the
variants
of
the
the
atom-wise
and
the
enamine
compounds,
and
we
are
they
essentially
in
in
the
pipeline
for
biochemical,
evaluation
or
or
is
spr
still
happening
or
or
possible.
C
For
the
spr
they
have
to
wait
at
least
three
months
for
getting
the
sensors.
So
biochemistry
is
the
one
that
we
we
have
to
follow
up
at
the
moment.
So
I
know
Indian
if
I'm
correct
leader
has
finished
with
those
and
I
mean
I,
see
50s,
and
he
was
doing
some
the
compass
that
you
recently
sent
us.
Yes,
if
I
remember
correctly,
but
let's
see
what
he
says
if
he
comes
over.
But
if.
D
C
A
Thank
you,
that's
good
and
we
yeah
we.
There
was
this
residual
question
again
that
he
can.
Maybe
he
can
address,
which
was
the
I
see
54,
you
hangs,
aiming
compounds,
but
also
Joe.
Last
time
was
mentioning
about.
You
know
evaluating
the
original,
hey
nerd
compounds
that
have
been
sent
to
check
the
you.
A
A
C
An
NTA
sensor
and
I
do
I'm
in
coupling
as
well
right
and
the
economies
that
they
are
having
issues
with
them.
Production
of
the
sensors.
C
A
C
Oh
yeah
I'm
trying
to
get
more
information
on
the
sensors
and
it
is
weak
soil.
You
know
we
have
another
backup,
but
again
the
system
will
be
an
APO
system
and
we
saw
there's
not
a
lot
of
correlation
between
binding
and
inhibition.
So
I
don't
know
how
much
we
want
to
pursue
that,
but
I
have
acquired
I,
think
it
was
on
Friday
I
inquired
about
new
lead
times
and
new
codes
for
the
NTA
sensors.
A
Okay,
yeah
because
the
the
spr
and
we're
doing
here
and
the
the
stuff
we're
doing
with
the
creoptics
wave
instrument,
just
like
at
fancy:
espion
we've
gotten
chips
for
those
because
they're
they're
strap
Aberdeen
chips
right.
So
that's
the
that's
the
coupling
mechanism
right
and
you
don't
have
protein
with
that
on
the
end
right,
you
haven't,
got.
C
A
A
A
C
You
know
I
was
in
a
good
point
in
terms
of,
and
so
I
wasn't
waiting
for
too
much
a
cn5
side,
the
one
that
are
the
fastest
ones
to
deliver
because
they
always
have
some
around
they
burn
with
the
cn5
tips
is
that
you
need
to
do
I'm
in
coupling
without
any
other
way
to
attract
the
protein
into
the
surface.
Only
the
bi
bi
intending
the
BH
and
mule
I.
Guess
it's
done
like
being
abruptly
change
the
pH
so
right,
right
yeah,
at
least
when
I
tried
it.
It
didn't
go
well.
A
Okay,
we've
had
quite
a
lot
of
luck
with
a
control
compound
versus
the
well
a
couple
of
different
proteins
that
consume
ATP.
We've
had
quite
a
lot
of
that
with
ATP
per
iodate.
There's
a
control
compound.
It's
been
quite
useful
that
I
don't
know
how
that
would
do
on
the
ligers
as
a
as
a
potential
spr
control
as
a
potential
binder,
but.
A
D
Back
it
used
to
be
a
classic
way
of
modifying
trnas,
so
the
terminal
Hydra,
the
terminal
3
and
three
prime
hydroxyls,
you
modify
with
periodate.
If
you
wanted
to
cleave,
generate
an
Altoid
and
then
use
it
for
mapping
with
trn8
band
on
the
protein
right.
A
Come
to
you
in
a
moment,
Adrian
for
for
an
update,
but
given
that
we're
on
crystallography
I
was
gonna
just
switch
over
to
Bart
in
case
there
are
any
updates
from
from
you,
Bard
or
or
from
interactions
with
the
the
guys
at
the
University
of
Kansas.
E
Yeah,
so
what
we're
working
on
right
now
we
sent
Kansas
the
protein
we
had,
which
was
mostly
E
coli
protein,
which
I
think
he's
been
talking
to
Laura
about
and
we're
having
the
same
results
that
they
had,
which
is
basically
I,
think
Unbound
structures
we
have
morem
or
D,
currently
being
upscaled
for
both
acetobacter
and
pseudomonas
and
those
are
being
upscaled
and
will
be
sent
as
soon
as
we
get
them
done.
E
I
saw
that
they
were
upscaled
last
week,
and
so
the
purification
should
be
going
this
week
and
then
we
also
have
we
started
working
on
the
mer
e
for
both
of
the
acetobacter
and
pseudomonas,
where
we-
and
you
know,
we
have
an
ad
luck,
getting
structures
of
those
previously.
So
we
are.
We
have
some
students
this
summer
from
Seattle
Children's
intern
project,
or
we
have
making
service
mutants.
So
they're,
gonna
they're
spending
this
summer
doing
site
direct
immunogenesis
and
making
a
bunch
of
different
surface
mutants
for
both
Murray's
from
acetinobacter
and
pseudomonas.
E
E
We
have
the
jos6
I,
don't
remember
what
else
if
you
sent
us
anything
else,.
F
C
Yes,
so
I
did
order
the
compounds
from
audience.
The
last
compounds
the
last
kids
I
ordered
them
for
us.
They
are
still
on
the
way.
C
C
C
E
F
C
C
G
I'm
I'm
happy
to,
although
although
Bart
was
also
yeah,
I
can
certainly
do
that.
F
Well,
I
think
part
I,
think.
The
point
here
would
support
once
things
sent
directly
to
Scott,
so
I
think
we
should
just
do
that.
We
can
order
from
from
by
Northeastern
to
sense
things
you
know
directly
to
Scott
from
Amy
I
think
that
would
be
to
some
I
think
that
would
be
the
simplest
thing
to
do.
Early
quicker.
A
All
right,
great,
so
yeah
last
time,
I
think
there
were.
There
were
11
compounds
that
were
looking
good
and
Adrian.
You
were
talking
about
five
of
them
yeah.
D
I'm
going
to
give
you
a
quick
verbal
update,
okay,
sorry
about
that.
First
of
all,
apologies
are
being
late,
Mid,
experiment
and
lost
track
of
time.
D
So
essentially
We've
we've
had
to
sort
of
regenerate
this
toxic
substrate.
So
let's
take
another
significant
amount
of
time.
So
we're
now
back
up
to
speed
with
that
we're
stuck
with
we
started
going
through
ways,
compounds
or
40s.
Six
of
them.
D
I
have
one
issue
slightly:
it's
the
amount
of
compound
we've
got.
So
if
we're
going
to
be
screening
at
the
similar
concentrations,
which
is
in
the
sort
of
500
micromolar
downwards
range,
we
are
going
to
have
a
limitation
with
volumes.
So
what
I've
been
having
to
do
is
to
basically
reconfigure
the
assay
to
take
into
account
adding
things
into
more
dilutes,
which
basically
means
adding
more
to
MSO
at
the
moment.
We're
just
making
sure
that
we
can
do
that.
D
So
I
actually
did
have
a
question
that
results
from
that,
and
that
is,
do
you
have
a
concentration
range
in
mind
for
these
particular
compounds
set?
In
other
words,
are
you
happy
for
us
to
go
up
that
high,
or
would
you
rather,
we
use
a
lower
concentration
range
which
will
be
easier,
but
will
it
be
useful
to
know.
A
Well,
these
are
mostly
derivatives
of
the
you
know,
original
atom-wise
and
enamine
compounds
that
were
found
to
be
multi-targeters
yeah.
We
don't
they
won't.
They
won't
be
strongly
inhibiting
I
wouldn't
have
thought
so.
They're
I
mean
they're
rather
like
the
ones
you've
seen
already,
where
you're
getting
ic50s
and
the
100
micro
molar
range
I
would
have
expected.
You
know
that
would
be.
That
would
be
the
best
we'd
hope
for
and
and
really
you
know,
the
idea
was
to
repeat
whatever
assay
it
was.
D
Okay,
right,
that's
fine!
So
now
I
know
the
other
thing
I
was
going
to
say
was
that
we've
also
in
the
background
we've
been
doing
other
things?
I've
I
did
Show
a
slide
a
few
talks
ago
about
a
diet
and
its
in
compound
up4a.
D
D
It
seems
to
be
a
specific
effect
in
that
the
other
ligases
are
a
lot
less
sensitive
to
that
and
out
of
well
curiosity
and
more
than
anything
else,
I'm
looking
at
the
other
by
nucleotides,
you
can
buy
so
AP
2A
3A
4A
5A,
to
see
if
there's
a
range
way,
because
my
logic
is
that
it'd
be
interesting
if
it
could
get
an
inhibitor
which
bridged
both
nucleoside
silver.
D
A
All
right
and
the
so
last
time
you
you
were
showing
us,
the
the
the
the
ic50
to
five
of
the
compounds
were
showing
the
hill
slopes
and
and
the
and
the
potencies
and-
and
he
said
that
there
were
another
six
compounds
where
you're
digesting
the
data.
Did
you
did
you
get
anything
from
that?
The
compounds
that
we
should
be
thinking
about.
D
We're
still
at
the
number
of
compounds
that
we've
got
I
mean
these.
The
rest
of
the
data
looked
like
you
had
very
high
hill
slopes.
We
suggested
that
there
was
a
very
complex
mode
of
interaction
between
the
protein
and
the
inhibitor
and
to
try
and
navigate
a
route
down.
Such
a
compound
will
probably
be
difficult
because,
ideally
you
just
want
a
nice
single
interaction
to
Target,
as
opposed
to
multiple
ones.
So
at
the
moment
we
basically
are
stuck
with
the
ones
that
we've
got.
A
Okay,
so
these
ones
were
the
ones
I
mean,
particularly
there
was
m17
m08
and
a19
were
looking
interesting.
Yeah,
particularly
mo8
there,
and-
and
there
were
there-
was
another
set
of
six
you
were
thinking
about.
Doing.
Has
anything
surpassed
these?
No?
No?
Okay,
all
right!
So
these
Remain,
the
interesting
ones,
particularly
the
you.
C
A
Send
okay,
these
three
I'm
70
and
MOA
in
May,
19.,
yeah,
yeah
right
all
right,
great,
okay
and
I
wasn't
sure
if
these
11
are
essentially
the
the
best
from
the
entire
enemy
Library
collection.
D
F
F
We
saw,
for
example,
combinations
of
Mercy
mirror
e
right
yeah.
So
so
in
theory,
you
in
this
case
you
know
we're
relying
on
pseudomonas
mirror
d
as
kind
of
our
initial
point
right,
and
so
the
question
would
be.
You
know,
for
example,
mirror
C.
If
you
screen
mirror
C
the
entire
Library
gets
near
C
or
near
e.
F
Would
you
identify
you
know
other
possibilities
that
might
be,
for
example,
CE
dual
inhibitors
I
mean
that's
just
a
thought:
I
mean
again
whether
you
even
have
stocks
to
do
that
kind
of
analysis
and
time
and
all
that,
but
just
just
as
the
point
that
these
sets
are
basically
coming
from
the
screening
of
the
full
Library
against
pseudomonosphere
d.
D
F
Yeah
I
mean
that's,
of
course,
and
I
would
say:
I
know
it's
just
a
matter
of
resources
and
whether
you
have
this,
you
know
the
stocks
available
to
even
do
another
single
point
against,
for
example,
mirror
C
or
very
but
anyway,
that's
that
was
just
the
point.
I
think
back
to
Matt.
These
are
the
hits
that
have
been
three
yards
down,
starting
from
the
full
screen
of
the
internet,
Library
against
mirror
D
yeah.
A
And
just
to
remind
everyone,
there
was
this
idea
of
this
nice
experiment
to
see
repeat
the
essay
in
the
presence
of
file,
see
the
inhibition
is
impacted,
and
the
reason
for
that
was.
We
were
interested
in
whether
or
not
some
of
the
compounds,
particularly
the
most
promising
one
I
think,
which
was
mo8,
was
acting
as
a
covalent
inhibitor
by
reacting
with
a
cysteine.
A
So
that
was
the
possibility
of
that
to
keep
it
on
there
on
the
to-do
list
as
possible
yeah
all
right,
okay,
great!
So,
if
is,
if
that's
everything
for
the
the
current
evaluation
of
compounds,
then
I
I
think
that's
everything
so
yeah
the
compounds-
the
the
e-way
sent
most
recently
wait.
One
second
I
think
I've
just
missed
those
so
back
down
here:
okay,
yeah
right
right!
So
so
these
are
you
in
U.S
shipments.
There
were
more
compass
on
this,
but
these
are
us
compounds.
A
Yeah,
which
again
are
derivatives
of
one
of
the
atom-wise
hits
so
yeah
for
these
compounds,
for
example,
it's
whatever
led
to
the
identification
of
aw53
is
something
of
interest
you
would.
You
would
want
to
repeat
that
for
these
compounds,
where
we're
just
playing
around
with
the
with
the
structures
a
little
bit
in
the
case
of
the
first
round
compounds
we're
going
to
see
solubility,
it's
use
of
the
kind
that
we're
very
familiar
with,
sadly,
and
in
the
second
round,
though,
we're
looking
at
more
soluble
compounds.
A
In
most
cases,
we're
trying
to
get
rid
of
some
rings
and
and
so
on
and
and
the
kind
of
the
really
nice
compounds
were
the
ones
that
the
UA
may
not
have
time
to
finish,
because
she's
got
a
hand
in
pretty
soon.
Those
are
the
ones
on
the
bottom
there,
but
they
remain
targets
for
us
because
they
are
predicted
to
be
more
soluble.
D
A
Yep
she
I
think
he
was
handing
in
on
the
15th
a
thesis
and
she's
giving
a
talk
on
at
the
end
of
the
month.
So
anything
of
that
kind
of
time
frame
would
be
very
helpful
for
her
to
show
the
compounds
of
have
done
something.
A
And
and
then.
A
They
are
it's
a
cheap
way
of
making
the
compound
more
soluble,
so
yeah
yeah,
but
a
better,
a
better
log
P,
but
we
may
it
may
hurt
yeah.
D
E
A
D
But
you
have
that
similar
configuration
of
two
carbonyls
within
amine
in
the
middle
yeah.
A
Yeah,
this
is
amazing
that
this
is
even
remotely
possible
to
get
this
compound.
It's
a
nice
one
yeah,
and
this
is
just
a
really
simple
way
of
trying
it
trying
to
deal
with
solubility
a
little
bit.
E
E
A
Make
it
basically
I
think
in
that
case
we've
got
no
there's
the
there
wasn't
anything
particularly
good
yeah.
That
was
completely
available
because
with
the
starting
point
here
is
where
the
the
this
CN
bond
is
a
is
a
carbonyl.
That's
the
chemistry
yeah,
so
it's
not
I,
don't
think
there
was
anything
suitable
for
that,
but
and
also,
if
that's
a
if
it's
an
unprotected
I
mean
it.
F
A
Messes
around
with
the
chemistry
you're
trying
to
do
so,
we
were
just
trying
to
use
these
as
a
kind
of
compromise,
so
we
shall
see
and
then
on
just
on
the
on
you
hang
stuff,
so
yeah
he's
his
he's
just
still
needs
that
one
ic50
of
his
aiming
compound
to
complete
his
table
of
results
for
for
this
work
and
then
to
to
sort
of
publish
the
our
attempts
at
improving
accumulation.
A
It's
it's.
A
set
of
compounds
that
have
pyridiniums
and
guanidiniums
on
the
side
chains
is
a
set
of
about
nine
compounds,
he's
going
to
be
making
just
to
sort
of
finish
that
work
off
so
to
extend
beyond
just
primary
amines
to
more
permanently
charged
things
and
then
we're
going
to
try
and
publish
that
work.
So
those
is
an
initial
targets.
We're
going
to
send
you
the
draft
of
the
cc4
car
proposal,
Joe
I
said:
we've
got
I
knew
I.
A
You
know
we're
going
to
do
that
last
time,
but
we
didn't
get
around
to
it.
So
we'll
send
it
to
you
ASAP
and,
and
then
you
hang
when
he's
finished,
with
those
charge
structures,
there's
going
to
be
completing
some
of
yan
yansen's
de
Nova
predictions
to
see
if
we
can
get
some
data
on
those
and
then
try
and
validate
what
yam
predicted.
A
Yeah
I'm
interesting
reagents,
here,
yeah,
okay,
all
right,
so
that
was
what
I
think
was
going
on
here.
So
you
and
you
hang
a
busy
making
compounds
or
or
writing
things
up.
Anyone
who
has
not
yet
had
a
chance
to
talk
who
would
like
to
raise
anything
anyone
else,
some
any
you
Laurie
or
or
Bob.
G
I,
don't
have
anything
specific
to
bring
up
at
the
moment,
I
we'll
say
I
connected
with
Adrian
Laura
and
Chris
offline
by
email
about
looking
for
some,
maybe
analogs
available
of
some
of
the
the
like
the
j06,
for
example,
I.
My
intention
is
to
work
with
Joe
to
get
him
to
have
a
look
at.
Maybe
so
it
doesn't
look
like
there's
anything
commercially
available
that
we
could
purchase
and
easily
kind
of
use
to
generate
SAR.
G
But
maybe
what
we
could
do
is
is
get
an
advanced
intermediate
and
make
a
couple
of
modifications
and
things
like
that
in
the
lab
right
that
that's
kind
of
the
plan
I
just
I
I,
it's
happening
just
a
little
slower
than
I-
would
like.
G
100
I'm
actually
also
just
sending
you
an
email
with
the
the
reviewer
comments.
So
we
got
reviewer
comments
back.
It
did
not
get
discussed
at
the
NIH
study
section
and
so
I
was
going
to
circulate
that
so
that
you
could
have
a
look
and
then
we
could
come
up
with
a
strategy
on
how
to
actually
resubmit.
G
B
That
regard
I'll
be
working
with
Lori
over
this
next
year
in
my
first
year
of
post
retirement
to
to
get
some
assistance
and
and
and
comments
for
resubmission
and
hopefully
be
able
to
super
size.
Some
of
the
students
that
are
going
to
be
working
with
her
I've
mentioned
that
I
think
to
to
Matt
in
in
email
correspondence,
and
hopefully
we
quarterly
coordinating
those
activities
with
what
this
group
is
doing.
D
A
Okay,
all
right,
okay,
good
anything.
Anyone
else
would
like
to
raise.
F
F
A
A
Yeah
best
of
luck
all
right
thanks
everyone
else
for
coming
along
great
to
see
you
all
and.