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0:00
Hi, this is Rumin Zhang,
a Research Scientist with Merck.
Today, I'll be giving a lecture
on the quantitative analysis
of receptor allosterism
and its implication
for drug discovery.
This lecture is based
on the review paper
we recently wrote and published
in the expert opinion
on drug discovery.
0:22
In this lecture,
we will cover six aspects.
First, I'll go over, with you,
the operational model
for receptor allosterism.
And then I'll provide
a high level classification
of receptor modulators.
Thirdly, I'll go over, with you,
the optimal screening
conditions for modulators.
And fourth,
we'll talk about a phenomena
we termed as beta
supremacy in allosterism.
And fifth, we will cover
the optimal assay design
and data analysis by
global curve fitting analysis.
Lastly, address the impact
of maximum system response,
Emax, on the parameterization
of receptor allosterism
and this lack of impact
on the structure-activity
relationship, or SAR ranking.
1:12
Shown is a schematic
for a general operational model
for receptor allosterism.
Let's focus on
the lower left side.
The R stands for receptor.
Recepted self may
have some basal level
or constitutive level
of receptor activity,
because a small fraction
of the receptor population
may adopt a preexisting
bioactive conformation
that can be ready to talk to
the signaling molecule proteins
Arrestins and so forth,
and they initiate some
biological responses.
So it has a basal level
we termed KAI,
as a level of basal
or constitutive
receptor activity.
And then to the right,
where you have agonist A binds
to the receptor for mean
a binary agonist
receptor complex, your AR.
That binary complex
also possesses
a level of activity
which is described as τA.
And of course, that activity
derives from the fact
that AR complex will
also isomerize
into a bioactive
confirmation AR star.
And then on the left,
go up from receptor to RB,
that B stands for
the modulator molecule,
separate from
the agonist molecule.
The modulator B can
form a binary complex
with the same receptor.
In this case,
it can occupy a site
other than the agonist
binding site,
we call this
an allosteric modulator.
But B also can bind
to the same site,
an overlapping site
with agonist,
and behave as an allosterically
competitive molecule.
So that RB binary complex
also may possess
some level of biologic
activity termed as τB.
In a fourth
thermodynamic circle,
if A and B
are mutually inclusive,
then they should be able
to form a ternary complex,
together termed ARB.
And that is the agonist
receptor and modulator
together forming
a ternary complex.
And that ternary complex
can have its specific biologic
activity described as τAB.
In the field,
τAB is often described
as a product of two parameters.
Beta times τA, meaning,
how many folds of change
relative to
the agonist activity, τA.
Well, that's the description
of the biologic activity
for the four receptor species,
R, AR, RB, and ARB.
Notice also when the agonist
or the modulator molecule
bind to the receptor,
they have certain affinities.
And those affinity constants
are described as KA or KB,
meaning the dissociation
constant of AR
or the dissociation constant
of RB molecule.
But in the presence
of each other,
that affinity constant
may be modified
by a factor termed alpha.
Thus in the presence of agonists
on the right side
AR forming ARB,
that binary affinity
can be different
from R forming RB
in the absence of A.
So the KB affinity constant
can be modified
by a fraction factor called
alpha or affinity modifier.
And likewise, by the principle
of thermodynamic linkage,
if the affinity of B
binding to a receptor
that's preoccupied
by A, AR to ARB,
if that affinity has been
modified by alpha,
then likewise, mutually,
the affinity of A
binding to the receptor
in the presence of B,
which is RB to ARB on that top,
that affinity will
also be modified
by the same fold of alpha.
So alpha is called
the affinity modifier.
