Ligand bias

Jacobsson, M. and Karlen, A. (2006) Ligand bias of scoring functions in structure-based virtual screening. Journal of Chemical Information and Modeling, 46, 1334-1343. 

Zidar, D. A. (2011). Endogenous ligand bias by chemokines Implications at the front hnes of infection and leukocyte trafficking. Endocrine, Metabolic Immune Disorders Drug Targets, 11, 120-131. 

TYPES OF BIAS IN THE CHEMOKINE SYSTEM 2.1 Ligand Bias... 

Figure 1 Bias in the chemokine system and other 7TMRs. Biased signaling describes the ability of a receptor to induce different signaling pathways or cellular events. Thereby, different ligands may activate different pathways via the same receptor (ligand bias, A), or the same ligand induces different outcomes at different receptors (receptor bias, B). Also the cell or tissue that "hosts" the ligand receptor interaction can modulate the induced signaling pathway (tissue bias, C).

Ligand bias can be evaluated by plotting two different cellular responses induced by the same concentration of agonist as functions of each other in order to obtain a bias plot (Fig. 2 Kenakin Christopoulos, 2013). This... 

This concept is demonstrated schematically in Figure 1.11. It can be seen that the initial bias in a system of proteins containing two conformations (square and spherical) lies far toward the square conformation. When a ligand (filled circles) enters the system and selectively binds to the circular conformations, this binding process removes the circles driving the backward reaction from circles back to squares. In the absence of this backward pressure, more square conformations flow into the circular state to fill the gap. Overall, there is an enrichment of the circular conformations when unbound and ligand-bound circular conformations are totaled. 

Indeed it might, but much experimental data would first need to be collected. The general idea would be to bias the test conformations of a ligand inside a binding site to be as near as possible to known X-ray crystal structures... 

Screening the molecular heterogeneity of receptor expression in endothelial cell surfaces is required for the development of vascular-targeted therapies. First, as opposed to targeting purified proteins as discussed above, membrane-bound receptors are more likely to preserve their functional conformation, which can be lost upon purification and immobilization outside the context of intact cells. Moreover, many cell surface receptors require the cell membrane microenvironment to function so that protein-protein interaction may occur. Finally, combinatorial approaches may allow the selection of cell membrane ligands in a functional assay and without any bias about the cellular surface receptor. Therefore, even as yet unidentified receptors may be targeted. 

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