Quantitative analysis of receptor allosterism and its implication for drug discovery

Published on December 31, 2015   57 min

Other Talks in the Category: Biochemistry

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.
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Quantitative analysis of receptor allosterism and its implication for drug discovery

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