►
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/57
On the call: Professor Matthew Todd, Dr Dana Klug, Yuhang Wang, Kato Leonard, Zige Bu, Shah Choudhury (UCL), Professor Chris Dowson, Laura Diaz Saez (University of Warwick), Lizbe Koekemoer, Frank von Delft (Diamond/Oxford), Dr Lori Ferrins, Dr Joe Eyermann (Northeastern University), Dr Jan Jensen (University of Copenhagen), Dr Chris Swain (Cambridge MedChem Consulting), Dr Jan Abendroth, Dr Bart Staker (SSGCID).
A
Right
so
welcome
everyone
to
ligay's
november
meeting,
and
I
will
just
get
the
right
page,
which
I
can't
now
find
one
second
one
second
and
then
I'll
make
sure
that
everyone's
got
the
right
right
screen
up
here:
okay,
okay,
so
welcome
everybody
and
and
a
bunch
of
things
for
us
to
talk
about
today,
I'm
not
sure
where
to
start.
Actually,
I
guess
if
anyone
wants
to
go
first,
that's
great!
Otherwise
we
can
take
it
in
order
of
the
of
the
actions
here.
A
If
anyone
has
anything
you
know
big
and
overarching,
they
want
to
say
initially.
That
would
be
fine.
So.
A
C
Sure
that
sounds
good
hello,
everybody.
My
name
is
jan
alvin
thought
I've
been
crystallogger
for
here
at
on
bainbridge
island,
just
to
the
outskirts
of
seattle.
C
For
about
15
years
close
to
15
years,
I've
been
working
for
ssgclv
since
its
inception,
we
are
in
our
15th
year
now
have
deposited
whatever
close
to
400
structures
for
sdgcid
and
peter
had
asked
me
to
take
peter
harrani.
My
colleague
here
had
asked
me
to
take
over
the
leadership
on
this
project,
push
some
structures
over
the
finish
line.
So
that's
what.
A
I'm
hoping
to
do
thanks.
I
think
we're
going
to
be
talking
about
one
of
those
today,
all
right,
I'll
I'll
dictate
the
screen
order.
So
I'm
matt
todd,
I'm
at
university
college,
london
and
we
have
a
lab
there-
that
with
a
few
people
who
are
looking
at
the
merly
gazers
as
a
project
and
background,
is
in
organic
chemistry
and
medicinal
chemistry
and
open
science.
D
E
F
Hi,
I'm
dana
I'm
a
postdoc
in
maths
lab
in
london
and
I'm
doing
mainly
synthesis
and
compound
design
great
and
then
next
is
lori.
G
Hi,
my
name
is
laurie.
I
am
a
research
faculty
member
at
northeastern
university
in
boston
and
I'm
a
medicinal
chemist
by
training
and
yeah
lovely
to
meet
you.
B
And
then
joe
hi
hi
john,
so
I'm
a
confrontational
chemist,
I'm
ex
astrazeneca,
I
was
an
estrogen
for
15
years,
worked
on
demure
ligases.
I'm
currently
have
a
couple
different
roles,
but
I'm
currently
a
visiting
sciences
in
at
northeastern
and
laurie's
lab
and
we're
working.
You
know
a
number
of
different
projects
together.
H
B
I
Oh
hi
yep
chris,
hasn't
worked
university
25
years
a
lot
of
that
doing
neoliberal
things,
the
last
15
or
16
years.
I
think
and
really
helping
to
support
biochemistry
input
and
some
structural
biology
input,
so
assay
development.
I
suppose,
and
then
structure
enabled
discovery
after
that.
J
Hi
everyone,
I'm
I'm
the
first
year
phd
student
in
math
group,
so
I'm
doing
some
synthesis
and
a
little
bit
computational
right.
K
B
L
You're,
a
great
company,
I've
got
no
bloody
idea,
frankfurt
crystallographer
at
diamond.
I
run
the
xcom
facility
and
sort
of
part-time
interested
in
amr
questions
they're
trying
to
help
as
possible
awesome.
Thank
you.
A
N
All
right
and
then
yan
are
you
joined
us,
yes,
so
yeah
jan
jensen,
a
computational
chemist
at
the
university
of
copenhagen,
so
we're
currently
working
on
trying
to
help
with
docking
studies.
I
don't
know
how
much
we're
hoping
but
we're
docking.
A
A
A
Okay,
okay,
so
I
guess
I'm
happy
just
to
go
through
some
things
and
and
try
and
speed
through
things
every
through
everything.
In
the
hour
I
mean
laura
one
of
the
the
first
thing
here
is,
I
guess
something
that
you
posted
quite
quite
recently
about
you
were
taking
some
of
the
atomized
compounds.
I
think
it
was
and
working
on
svr
binding
assets
is
that
right.
E
With
multimedia
yeah
I
was
gonna,
I
wanted
to
optimize
the
asa
and
then
run
the
voice
compounds
library
against
the
mirror,
cd
and
e,
but
they
are
not
happy
on
the
cn5
sensor,
so
I
bought
a
new
sensor.
They
sent
me
a
message
that
it
was
shipped
yesterday.
So
after
this
meeting,
I'm
gonna
go
to
the
to
the
area
where
we
have
all
the
others
and
I'm
gonna
see.
If
it
is
there
in
that
case,
then
I
will
be
doing
the
essays
trying
to
do
this
with
the
new
sensor
next
week.
Okay,.
A
Okay,
awesome
is
this:
I
forgive
my
ignorance.
Is
this
the
first
time
we've
had
an
spi
essay
for
them
like?
Is
it.
E
E
A
Yeah,
okay
and
becker,
I
think,
has
been
delayed.
Another
meeting
but
is
working
on.
A
I
F
She
yeah
she
emailed
me
and
said
she's
having
some
plate.
Reader
issues
and
she's
got
preliminary
data,
but
nothing
final.
Yet
she
said
so
maybe
she'll
come
later
and
say
more
about
that.
But
that's
the
latest
I've
heard
from
her.
E
I
E
I'm
not
gonna
go
into
too
much
detail
on
how
the
essays
work
you
can
ask
him
on
on
the
site,
but
this
would
be
the
essay
for
me
or
d
is
different
coupled
enzymes
and
they
are
measuring
asteroids
and
fluorescence
as
well,
and
then
this
would
be
the
one
for
mu
e
again,
the
same
system
with
the
same
coupled
enzymes
and
the
same
absorbance
readout
and
fluorescence
readout,
and
they
have
been
testing
both
spectrophotometric
and
fluorometric
essays,
but
the
feromatic
one
seems
to
be
the
the
ones
working
better.
E
E
Because
the
microliters-
I
think
this
is
wrong,
so
he
gave
me
two
slides
one
for
50
and
another
one
for
20.,
but
these
are
the
results
for
20..
E
Exactly
it
would
be
really
good
for
doing
the
hydrogen
screens
and
be,
you
know,
be
able
to
screen
more.
Oh,
that's
great.
I
Yeah,
I
think
the
aim
is
once
the
plate
reader
is,
is
serviced
or
we
switch
plate.
Readers
he's
pretty
confident,
that'll
go
down
to
10
microliters
and
that
that
I
think
then
that's
the
elf
format.
So
we've
got
that
with
the
parameters
and
the
z
prime
for
them,
which
I'm
keen
for
that
to
be
very
soon
before
the
end
of
the
month.
Okay,
communicate
that.
A
I
I
A
The
the
european
leaf
actually
interested
in
in
this
very
much
and
just
wanted
some
more
information
on
the
on
the
ability
to
run
high,
throughput
assay,
and
so
that's
that's.
This
work
is
crucial
for
that.
D
I
I've
just
said
that
this
is
fantastic
news.
I
think,
having
access
to
the
european
league
factory
will
be
a
really
interesting
exercise.
A
Awesome
all
right,
yeah,
sorry,
is
there
anything
else.
You
wanted
to
add.
E
A
Okay,
any
other
questions.
A
There
you
go
all
right,
excellent,
and
so
there
was
one
question
which
came
up.
You
hang
and
I
were
talking
earlier
today
and
I
guess
we
were
wondering
about
the
the
known
azad
act
that
he
shipped
to
both
ssgcid
and
also
you
guys.
I
mean.
Is
there
advantage
in
in
in
measuring
the
activity
of
that
supposedly
known,
active
versus
dna?
Or
is
that
I
mean
just
to
make
sure
it's
fine,
that
we
have
a
positive
control
and
that
it's
active
against
both
joe.
B
I
guess
yeah,
I
guess
the
question
becomes
actually
which
species
you
actually
have,
because
I
don't
know
I'm
a
little
confused
about
it.
I
think,
as
far
as
I
know,
there's
no
pseudomonas
assays
for
your
c
or
d
or
e
and
and
warwick
so
sorry,
sorry
joe,
that
that
there
are
essays
for
all
of
those
but
yeah.
But
okay,
okay,.
I
B
Yeah,
but
I'm
just
okay-
I
don't
want
to
I'm
not
going
to
get
into
old
history
here
about
compounds
that
haven't
been
assayed
for
forever
so
anyway,
but
yeah.
If
there's
I
mean,
I
think,
if,
if
there's
an
assay
for
for
pseudomonas
or
e
coli
in
your
d,
it
would
be
good
to
get
the
az
compounds
acid.
Yes,
because
we
because
the.
A
Paper,
the
the
you
know
your
paper
is,
is
just
mercy
right,
that's
correct!
Okay,
so
I
mean
interesting
data.
If
it's
potent
against
another
right,
okay-
and
I
guess
I
wanted
to
ask
people's
opinion
on
the
on
the
atomized
compounds-
I
mean
if
if
this
is
a
reasonably
high
throughput
assay
and
it's
running,
then
is
it
worth
just
having
to
go?
Those
compounds,
the
ones
that
were
found
to
be.
L
I
said
one
last
question
to
joe:
would
you
expect
those
compounds
to
have
some
activity
against
dna.
B
B
Enough
that
that
you
would
hope
that
there'd
be
some
activity.
So,
yes,
thank
you
in
terms
of
enf,
I'm
not
so
sure.
B
Obviously
be
interesting
to
get
you
know
a
a
a
mere
e
data
point
as
well.
D
A
Yeah,
okay,
so
yeah
eugene's
compound
should
be
active
against
more
than
one.
I
mean
that
that
would
be
very
nice
he's
also
making
the
other
main
a
z
compound
and
a
backup
compound
too
so
there'll
be
more
coming.
You
can
briefly
mention
this
in
a
minute,
but
but
yeah
I
mean,
as
we
generate
these,
you
know
we
don't
want
to.
We
don't
sort
of
send
small
numbers
of
compounds
if,
if
that's
a
drag,
but
but
if
the
combat
is
being
run
anyway
and
we
can
slot
those
in
that
would
be
great.
A
So
with
the
atomized
compounds
I
mean
we
have
binders
right,
we
don't
know
how
good
they
are.
Is
it
worth
just
trying
them
in
a
biochemical
assay
to
see
what
happens?
O
I
Mean
honestly,
the
astrazeneca
stuff
we've
ever
done,
we
would
have
done.
You
know
we
had
the
mere
that
those
pseudomonas
muir
ligase
essays
done
15
years
ago.
That's
when
we
got
the
comp
when
we
had
the
reagents
from
roger
levesque.
You
know
so
they
exist.
What
we
don't
have
is
the
paperwork
to
allow
us
to
work
on
the
compounds.
Yet
you
know
I'm
still
pushing
that
through.
B
Right
yeah,
but
you
have
you,
have
you
have
your
hands
compound,
so
I
mean
that's
an
easy
compound,
so
that's
ready
to
go
so
it's
a
question
of
you
know.
Timing.
Do
you
want
to
wait
for
the
az,
the
3az
compounds,
or
do
you
want
to
you
know,
move
forward
with
the
compound
you
have
in
hand
from
johan's
lab.
B
I
I
think,
on
the
atomized
compounds
based
on
laura's
data,
the
crystallography
right
I
mean
they
don't
seem
to
be
competitive
right.
So
I'm
not.
I
think
the
spr
essay
is
going
to
be
just
finding
out.
You
know
binding,
and
maybe
I
don't
know
what
kind
of
competition
even
laura
can
do
in
the
spr
assay
itself,
but
I
think
on
the
biochemical
side,
I
think
you're
it's
going
to
be
might
be
a
big
challenge.
C
All
right,
I'm
not
sure
which
compounds
are
being
discussed
here,
but
we
received
three
compounds
and
tested
them
against
mirror
c
and
mir
d
from
pseudomonas
and
acetobacter
and
they
all
were
positive
with
good
shifts
in
thermal
flow
assays
for
mirror
c,
but
they
didn't
show
any
shifts
at
all
for
me
or
d
yeah.
That's
we're
talking
about
biochemical,
yeah,
yeah,
yeah,
yeah,
yeah,
right.
B
Well,
I'm
a
little
confused
here,
john
so
you're
doing
your
biochemical
assays
that
city.
I
thought
these
were.
B
C
These
three,
actually,
I
don't
know,
is
az22az13
and
az26
yeah.
Those
those
are
the
compounds
that
you.
C
A
C
C
B
C
A
B
Yeah,
sorry
about
that,
maybe
just
go
back
to
pres,
not
not
full
screen
mode.
I
guess
yeah,
sorry.
It
is
in
just
standard.
C
Okay,
so
the
first
two
lines
here,
the
this
is
pseudomonas.
This
is
acinitobacter,
137
is
mirror
c
and
17938
is
mir
d,
and
these
are
the
three
compounds
that
were
tested
in
the
dsf
assay.
We
got
very
nice
strong
shifts
for
the
two
mirror
seas
and
got
virtually
no
shifts
at
all
for
the
mirror
ds
again.
These
were
binding,
assays
no
biochemical
assays,
but
you
would
assume
that
by
chemical
assays
would
require
a
positive,
binding
assay
unless
there
are
some
conditions
that
we
didn't
consider
that
we
need
to
pre-incubate
with
a
cofactor
or
something.
B
B
C
B
And
that's
all
three
yeah,
so
so
actually
in
just
I'm
curious
here.
So
is
this
in
the
presence
this
is
okay,
so
one
of
the
discussions
that's
been
going
on
a
little
bit
is
the
dynamics
of,
for
example,
your
d.
B
So
if
you
look,
if
you
look
at
the
literature,
there's
an
open
forum
and
then
basically
when
you
have
like
atp
bound
and
you
get
more
of
a
closed
form,
so
I
guess
in
the
question
here
would
be
a
little
bit
about
you
know
the
dynamics
and
and
these
you
know
whether
these
are
inducing
you
know
the
closed
form
of
your
d
or
not.
B
So
anyway,
that's
that's
one
of
the
things
around
your
d.
I
know
there's
been
some
discussion
on
on
github
about
this
and
also
there's
papers
been
published
about
the
dynamics
of
your
d,
but
you
would
have
hoped
that
you
know
the
potency
of
these
compounds.
You
know
spirited,
but
enough
to
maybe
induce
you
know
just
this
binding
and
closing
of
near
d,
but
evidently
not
oh
yeah.
A
Did
we
have
data
of
this
kind
with
you
hank's
compound
the
the
other?
It's
another?
It's
not
the
same.
Is
it
am?
I
am
I
confusing
myself.
C
A
If
you
were
able
to
merge
this
with
that
compound,
that
would
have
a
full
set
here.
That
would
be
really
interesting.
A
C
A
B
G
B
It
was
done
in
the
presence
of
adp,
for
example,
and
you
know,
would
you
be
able
to
see
any
competition
any
kind
of
shifts
and
is
that
at
all
make
sense
or
not
to
try.
C
I
C
B
C
C
So
this
one
here,
it's
a
structure
that
I
solved
just
very
recently
whenever
a
crystallographer
finishes
up
a
structure
he
or
she
sends
it
off
to
a
colleague
for
peer
review
where
the
colleague
goes
through
the
model
atom
by
atom
and
double
checks,
it
that
it's
all
good
and
then
it
gets
deposited
to
the
pdb
or
forwarded
to
our
collaborator.
C
C
It's
got
two
copies
in
the
asymmetric
unit,
which
do
a
little
bit
of
this
sort
of
wobbling,
opening
and
closing
between
the
two
of
them,
and
my
hope
is
that,
within
like
two
or
three
weeks,
it's
ready
for
delivery
to
you
guys
and
the
pdb.
C
The
next
one
here
that
is
the
acetobacter
and
that
has
been
deposited
in
the
pdb
with
7s
ir
as
the
pdb
gold,
not
x,.
I
C
We
don't
have
many
crystals,
so
it's
not
that
I
have
a
lot
of
crystals
where
we
can
soak
them
in.
I
think
chances
are
very
low.
Chances
are
a
lot
higher
with
mirror
c,
and
these
actually,
the
the
crystallization
with
all
three
compounds
and
the
mirror
c
of
which
we
have
a
lot
of
is
actually
is
already
going
on
the
other.
So
sorry,
I'm
taking
over
the
presentation
here
so.
G
C
So
I
wanted
to
wait
for
your
advice,
what
to
do
with
it
and
we
can
do
anything,
but
once
when
the
protein
is,
is
used
up,
it'll
take
a
while
until
we
have
resupply.
So
I
want
to
use
it
wisely.
B
So
I
I
would
think
I
don't
know
I
mean
getting
a
structure
of
acetobacter
one
of
the
compounds.
In
your
c
I
mean
again
that
kind
of
chris
swain
was
talking
about
just
kind
of
building
out
a
portfolio
here,
even
though
it's
I
mean
we're
trying
to
get
dual
inhibitors
against
two
muralia
gases
at
least
getting
a
second
species
against
mere
sea
structure.
I
think,
would
be
be
valuable.
B
A
A
I
mean
it's,
you
know
absolutely
absolutely
absolutely
absolutely.
Hopefully,
people
on
the
school
want
to
have
a
pop
of
that,
because
it
seems
quite
important
to
me.
B
A
C
B
A
All
right
so
we've
talked
about
most
of
those.
I
if
I
don't
think
I
said
already
it's
on
me
to
contact
out
wise
to
run
through
the
results
that
we
got
from
the
soaking
and
check
what
they
have,
what
they
calculated.
So
I
haven't
had
a
conversation.
Yet
sorry,
but
it
will.
A
You
hang
was
just
as
an
update.
Is
that?
Okay,
if
I,
if
I
do
this,
because
we're
just
we're
running
a
little
shorter
time,
you've
prepared.
A
Of
some
services
that
you've
been
doing
so
to
to
try
and
access
the
the
other
aez
compound,
you
hang
had
a
really
nice
solution
to
getting
this
really
difficult
intermediate,
which
is
solved,
and
now
he's
got
a
beautiful
one
gram
of
this
intermediate
over
here,
and
so
we
can
attach
a
bunch
of
different
things
onto
this
position
and
we're
going
to
go
for
the
az
compound
first
and
then
there's
a
little
snafu
with
a
solvent
attaching
in
its
place,
which
we're
currently
dealing
with,
and
then
the
idea
is
after
that,
after
we've
got
that
problem
solved
to
then
I
mean
use
this
compound,
obviously,
but
also
to
convert
the
oh
to
the
amy
and
he's
got
a
nice
double
step
approach
here,
which
is
you
know,
you've
got
to
pray
a
little
bit
to
the
gods
of
chemoselectivity
that
that'll
work,
but
it's
not
a
bad.
A
It's
not
a
bad
punk.
There
are
ways
around
this
if
it
doesn't
work
of
making
the
diamine
initially-
and
this
is
the
backup
compound
also
from
azer
paper
and
and
this
could
also
be
converted
to
the
amine
using
this
approach.
So
things
are
in
progress
and
eugene's
been
doing
some
tricky
chemistry,
but
we
we
we're
pretty
confident
that
we're
going
to
have
the
other
reset
compound
pretty
soon.
A
Okay
and
for
those
of
you
not
familiar
with
what
making
this
a
mean,
so
we
can
try
and
make
the
compound
active
against
wild
type
organism.
J
For
for
the
compound
13
for
the
compound
13
aiming
derivative,
just
just
this
side,
yeah.
G
J
For
this
side
we
would
just
know
that
we
just
got
the
information
from
yen
right
like
that,
it's
it's
alcohol,
it's
alcohol
form
did
not
got
goods
shipped
on
the
binding
essay.
So
we're
already
expecting
to
get
a
good
data
from
this
struct.
The
amine
derivative.
J
B
B
B
But
either
neither
one
of
those
had
good
gram-negative
activity
or
wild-type
very
negative.
A
B
A
The
I
mean
the
obvious
possibility
here
is
that
this
carbonate
group
is
cleaved
and
the
amine
makes
no
difference
at
all
right.
So
I
guess.
B
A
Well,
yeah,
and
I
mean
if
you,
if
you
go
to
the
bacteria,
correct
yeah,
that's
true,
that's
true!
You
have
compound.
It's
just
got
the
amine
there.
So
there's
no
way
you
can
have
a
problem,
yeah,
okay,
great
all,
right
thanks
and
then
I
guess.
The
next
thing
that
has
been
generating
a
bit
of
discussion
was
the
the
predictions
from
from
yan
and
the
poses
that
that
were
generated
and
and
which
were
posted
earlier.
A
C
A
So
I
guess
the
the
structures
that
were
that
were
deemed
to
be
the
most
promising
which
were
commercially
available
were
the
ones
here
we've
spotted
the
two
are
very
similar,
maybe
aren't
needed.
The
poses
that
came
out
are
really
interesting
in
the
sense
that
the
so
this
is
the.
I
think
this
is
the
stuff
that
you
did.
Are
you
hearing,
so
the
the
yellow
is
the
original
azad
compound
and
the
the
greens
here
are
the
predictive
compounds
so
adjacent
and
a
little
bit
overlapping,
but
a
bit
distinct?
A
G
N
Not
like
a
you
know,
an
actual
like
you
know,
crystallization
screen,
so
they
can
only
bind
what
we
tell
them.
So
that
says
nothing
really.
So
so
it's
really
about
whether
they
make
the
contacts
we
think
they
should.
N
And-
and
I
don't
have
really
neither
casper
and
I
have
really
the
expertise,
so
we
just
threw
it
out
there
and
in
terms
of
the
protonation
states
which
were
discussed,
so
we
now
use
big
prep,
which
basically
tries
all
possible
protonation
states
and
protomers,
and
we
basically
just
pick
the
one
with
the
best
the
best
docking
score,
and
so,
if
that's
not
realistic,
then
maybe
we
should
disregard
it.
Although
I
have
to
say
that
there
are
many
examples
of
sort
of
a
pro
nation
state,
that's
not
likely
in
solution
right.
N
That's
that
sort
of
picked
up.
You
can
pick
up
a
proton
or
you
can
lose
a
proton.
When
you
bind
the
active
site,
you
you
take
a
hit
in
the
docking
score,
which
is
not
included,
but
I
mean
there
are
plenty
of
examples
where
sort
of
an
unusual
protonation
state
is
found
in
the
in
the
in
the
actual
dark
yellows.
B
Yes,
no,
no,
no,
no
they're,
not
I
mean
so
a
pyridine
pka
I
mean
chris
swing
can
step
in
here,
probably
as
a
better
physical,
organic
chemist,
but
the
pka
of
pyridine
is
what
four
and
a
half
five
or
something
like
that,
so
at
a
neutral
ph
or
in
water.
You
know
that
again
was
assuming
we're.
You
know
at
physiological
ph
of
7.4.
B
B
Yeah,
but
it's
pretty
hard
to
get
the
pka
of
appearing
up
to
I
mean
you
know
in
one
one
ph
union
is
a
factor
of
10
right
so
ph.
If
you
have
a
pka
of
six.
That
means
you,
basically,
your
your
tenfold,
your
10,
your
one
tenth
of
the
population
of
in
terms
of
what's
what's
present.
Now
you
can
talk
about
the
shoddy
a's
and
the
actual
binding
event.
Pulls
it
out
of
solution,
et
cetera,
et
cetera,
et
cetera.
So
so
it's
just
it's
fine!
You
will.
You
will
find
cases.
B
You
know
your
your
you're
playing
a
lot
of
roulette
here
if
you're
hoping
to
bind
a
protonated
pyridine
and
just
also
on
some
of
the
you
know
on
the
scoring
I
mean
I
just
live
with
this
forever
scoring
the
electrostatics
in
terms
of
the
contribution
of
scoring
functions
tend
to
dominate,
and
so
when
you
have
salt
bridges,
it
will
make
your
scores,
look
a
whole
lot
better
and
if
you're
not
doing
you
know
even
the
solvation
terms
that
are
out
there,
these
kind
of
what
do
you
call
it?
B
They're
not
true,
you
know,
you're,
not
running
free
energy,
perturbation
kind
of
calculations,
those
solvation
terms
are
kind
of,
not
so
great,
so
anyways.
It's
fine,
I'm
just
trying
to
point
out
that
those
are
some
of
the
risk
factors
with
these
compounds
that
your
scores
are
being
dominated
somewhat
by
electrostatics
and
you're.
B
N
Yeah-
and
I
I
don't
disagree-
I
mean
it's
you're,
absolutely
correct
in
that,
so,
if
you're
trying
to
if
you're,
trying
to
narrow
it
down,
I
mean
I
I
imagine,
these
compounds
are
fairly
expensive.
If
you're
trying
to
narrow
it
down,
throwing
out
an
unlikely,
protonation
state
is
a
very
good
metric
sort
of
for
for
excluding
something
if
you,
if
you
have
other
compounds
with
a
more
sort
of
realistic,
protonation
yeah.
I
absolutely
agree
with
that.
A
What's
the
you
were
mentioning
joe,
the
the
salt
bridge
with
the
with
one
of
the
residues?
What's
the
motif
in
these
molecules,
that's
doing
that
because
they're
all
quite
different
here.
What's
the
what's
the
interaction.
B
B
So
if
you
look
at
like
in
the
top
row,
for
example
the
top
row,
the
fourth
compound
from
the
right
that
compound
that
pyridine
is
protonated
and
you
have
the
basically
the
nh
of
the
pyridine
interacting
with
the
aspartic
acid
side
chain,
okay,
and
so
that
you
know
that
part
of
that
contribution
to
that
glide
score
is
coming
from
the
electrostatic
interaction
between
the
positive
charge
on
the
pyridine
and
the
negative
charge
of
the
aspartic
acid
side
chain,
and
that's
just
that
makes
your
score.
B
Look
like
you
know
it's
a
it's
a
better
scoring
compound,
but
the
likelihood
that
that
pyridine
is
protonated
is
low.
So
I
that's
just
what
I'm
saying
that
makes
that
a
risk,
and
so
I
would
be
looking.
You
know.
You've
done
a
lot
of
work
here
and
done
all
the
docking
I've.
Just
when
you
go
looking
through
the
results.
I
would
just
think
about.
You
know
which
of
the
ones
are
compounds
that
are,
you
know,
forming
salt
bridges
and
then,
if
they
are
what's
the
protonation
state,
and
some
of
these
are
okay.
B
Some
of
the
piperazines
pippazine's
like
compound
on
the
top
left
is
definitely
protonated.
It's
not
it's,
never
doubly
protonated.
If
there's
a
logical
ph,
it's
the
terminal
of
nitrogen
and
it'll
be
protonated,
that's
the
one
that
has
the
more
basic
pka
and
that's
fine
that
you
know
that
will
be.
That
will
be
protonated
physiological
ph,
and
so
you
know
that
in
terms
of
its
score,
is
the
interaction
is
fine.
It's
a
question
of
you
know
that
score
of
minus
eight
is
still
again
being
dominated
by
an
electrostatic
interaction.
A
No
because
we
need
to
do,
we
have
to
have
a
time
for
what
we're
doing
with
these
molecules.
Right
and-
and
you
know
we
want
to
buy
some
some
stuff-
that's
predicted
to
be
good
because
it's
important
to
get
experimental
data
to
to
so
we
know
you
know
how
these
predictions
are
doing,
but
we
just
want
to
be
sure.
That's
all
as
best
we
can
so
the
points
you're
making
very
good.
D
N
A
N
It
definitely
won't
be
protonated
in
solution,
we're
arguing
about
whether
it's
protonated
in
the
yeah,
but
even
if
it's
unprotonated,
this
will
have
a
high
long
t
so
I'll
be
worried
about
the
solubility
of
that
particular
one.
A
B
I
mean
the
the
critical
thing
here:
matt
I
mean
you're.
I
think
because
I
recall
maybe
a
physical,
organic
synthetic
chemist,
and
so
I
think
you
know
your
your
pka
pretty
well,
you
can
look
at
molecules
and
know,
what's
going
to
be
protonated
and
not
be
protonated,
and
so
that's
that's
the
first
step
really
is
you
know
this
is
always
again,
jan
I'm
not
please.
Please
don't
take
this
the
wrong
way,
but
just
you
know
when
you
use
these
automated
programs,
especially
and
I've,
just
dealt
with
this
many
many
times
and
the
schrodinger
software.
B
You
know
their
pka
predictions.
What
things
get
protonated
is
not
always
the
best
and
you
just
gotta
use
your
science,
your
of
understanding
what
pkas
are
of
different
groups
and
what
should
and
should
be
protonated,
like
I
said
you
see
in
these
things
where,
like
pipperzines,
get
diprotonated
one,
the
chance
of
a
piperazine
being
diprotonated
is
like
nil
and
the
pka
of
the
pyridine.
So
again
I'm
gonna
stop
here
I
gotta
stop.
We
got
time
taking
up
too
much
of
this
meeting.
A
I
guess
what
I'm
what
I
meant
was
the
green
structures
we're
looking
at
here.
I
just
it
would
be
nice
to
see
what
the
protonation
state
is
that
is
leading
to
the
binding
and
and
therefore
how
we
can
triage
these
suggestions
easily
right,
so
we
can
trigger
by
p
and
we
can
trigger
by
cost.
But
how
do
we
treat
by,
for
example,
realistic,
pronation
state?
I
think
you
have
to
look
at
them
one
by
one.
That's
what
I
mean
bound
into
the
active
site.
That's
what
I
mean.
B
I
uploaded
it
the
maestro
file
this
morning
and
that's
when
I,
you
know
kind
of
started
to
look
at
them,
and
so
there
is
a
I
can
post
a
maestro
file
or
there
is
a
maestro
file.
I
think
that
john
already
posted
to
the
github,
that's
where
I
pulled
it
down
from
okay,
and
so
you
can
just
pull
that
into
and
just
throw
it
into
maestro
and
schrodinger,
and
you
can
look
at
the
structures
and
you
can
see
that
what
their
protein,
which
ones
are
protonated
and
make
attachment.
N
A
N
Well,
actually,
no,
so
so
not
from
the
not
from
the
purchasable
compounds.
So
these
are
all
the
compounds
with
a
score
lower
than
seven,
which
is
basically
what
we
think
is
is
reasonable
for
binding.
So
that's
that's,
basically,
all
the
ones
we
found
so
yeah
from
from
that
that
are
purchasable
from
this
from
this
library,
okay,
okay,
anything
any
anything
else
will
have
a
lower
score
that
we
deem
sort
of
likely
to
be
non-binders.
B
N
N
If
you
go
further
up
in
the
issue,
there's
a
set
of
about
500
compounds
that
brian
shortcut
measured
for
a
kinase
and
we
basically
just
compute
not
not
in
this
issue
the
original
issue
right
right
yeah,
so
we
basically
computed
sort
of
the
likelihood
of
being
a
good
binder
based
on
the
glide
score
and
basically
it's
in
if
it's
less
than
-7
it
has
about
a
50
50
chance
if
it's
higher
than
seven
it
has
like
a
25
percent
chance.
B
Yeah-
and
these
are-
I
guess
I
look
at
these
as
most
of
these
are-
I
would
put
them
in
most
of
these
in
the
fragment
class
they're
relatively
small.
Most
of
these
are
microwaves-
I
assume
were
probably
under
300
or
not
much
above,
and
so
you
know,
these
being.
You
know
a
10,
micromolar
or
even
50,
micromolar
inhibitor,
I
mean
that's
still,
and
these
are
all
novel
right.
So.
B
I
don't
know
I
wouldn't
necessarily
I
mean
I
understand
where
you're
coming
from
it's
all
logical
in
terms
of
using
that
shortcut,
kinase
thing,
but
I'm
not
sure
I
would
just.
B
I
might
be
a
little
bit
more
aggressive
here
in
terms
of
thinking
about
some
of
the
other
compounds
that
might
be
a
little
bit
lower.
You
know,
okay,
what's
the
what's
the
difference
between
minus
six
and
minus
seven,
I
guess
is
my
question
when
you
look
at
the
poses
so
something
you
might
think
about.
N
Yeah
we
can,
we
can
throw
up
more
with
with
word
score.
It's
just
our.
The
only
data
we
really
have
to
go
on
is
the
shortcut,
and
it
just
drops
from
you
know,
50
to
25.
When
you
go
below
seven,
that's,
basically,
all
we
have
to
go
by.
B
A
The
background
thing
here
is
that
it
would
be
great
to
get
to
a
point
where
we're
happy
to
buy
commerce
to
validate
the
the
the
predictions
here.
That's
all,
but
we
need
to
be
sure
before
we
do
that,
all
right
so
yeah,
that's
that's!
The
most
key
issues
have
been
talked
about
here.
I
think
there's
a
bunch
of
other
older
actions
here,
a
bunch
of
other
smaller
things
here.
E
E
E
E
That's
fine.
I
think
we
should
be
fine,
but
yeah
yeah.
You
know
it
just
depends
on
how
it
goes
with
the
crystal,
but
yeah
anyway,
I'm
working
on
it
and
I
hope
we
can
have
it
soon
set
it
up.
Yeah.
A
And
laurie
just
a
quick
question
about
the
cyclica
input.
I
guess
we
we
have
invited
cyclical
to
the
meeting,
didn't
make
it
today,
but
maybe
at
a
future
one.
G
Yeah,
I'm
still
having
issues
in
terms
of
trying
to
get
any
kind
of
agreement
through
I'm
actually
going
to
reach
out
to
them
today
and
see.
If
I
can
organize
a
meeting
and
just
see
if
there's
a
way,
we
can
push
this
through
some
other
way.
Okay,.
J
So,
just
just
about
one
minute:
sorry,
just
about
the
young's
suggest
and
joe's
suggestion
do
we
need
to
take
the
over-protonated
structures
and
manually
fix
it
fix
the
ph
protonation
state
and
then
like
redox,
so
that
we
won't
miss
any
potentially
useful
structures.
J
N
J
J
What
what
if,
what
if,
after
you
remove
the
protonation
state
and
and
it
got
a
different
pose
in
that
in
that
pocket
and
then
like.