Allosteric Targets For Drug Discovery And Future Trends

proteins represent a growing class of potential therapeutic agents. With continued progress in the elucidation of the three-dimensional of both the high and low affinity states of allosteric proteins, opportunities to

Figure 9.15. Schematic outline of the basics of allosteric drug design in li-gand agonists and antagonists.

design state-specific synthetic effectors will become increasingly feasible. As opposed to designing drugs that bind directly to an active site, which can often be limited by the need to generate molecules with receptor affinity that is severalfold that of the natural substrate, allosteric effectors offer the unique opportunity of binding to a location that is removed from the substrate binding site, and hence will elicit an effect (e.g., destabilizing an allosteric protein's active state), regardless of the concentration of endogenous substrate present. In addition, allosteric binding sites offer a potential for greater specificity for target proteins

Heterotropic activator stabilize R state

State active

R-T Equilibrium

State active

T State inactive

Heterptropic inhibitors stabilize T state

Figure 9.16. Allosteric drugs could stabilize either the R or T state in a Monod-Wyman-Changeux type allosteric enzyme.

proteins represent a growing class of potential therapeutic agents. With continued progress in the elucidation of the three-dimensional of both the high and low affinity states of allosteric proteins, opportunities to

Table 9.1 Allosteric Protein Targets and Small Molecule Effectors

Allosteric Targets

Description

Allosteric Effector(s)

Hemoglobin

HIV reverse transcriptase

HIV fusion proteins

Proteases and protease zymogens

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