Screening Allosteric Modulators with Analyze
An allosteric modulator is a molecule that influences a target receptor by binding to an allosteric site that is topographically distinct from the orthosteric or primary binding site. While the main principle underlying receptor-based drug discovery is optimization of molecules toward the orthosteric site, targeting an allosteric site can have potential advantages. Namely, allosteric drugs can amplify (or attenuate) the effect of endogenous ligands, thereby working with natural signaling mechanisms rather than causing activation independently which can lead to desensitization. In addition, allosteric sites tend to be less conserved between receptor subtypes and therefor offer the potential for drugs with greater selectivity and less side-effects.
The characterization of allosteric modulators requires significantly more effort than traditional drugs as the models contain many more parameters that, in-turn, require more sophisticated experiments and data analysis. While it may be sufficient to use XC50 and maximum efficacy for routine screening, modulator-specific parameters should be obtained for SAR ranking, PK/PD modelling, and dose prediction. In this case, the recommended approach is to generate a matrix of receptor activities, by varying both agonist and modulator concentrations, and fit a 3D allosteric model function by non-linear regression.
This analysis can be time consuming and error prone due to its complexity. Analyze™ accomplishes all the steps involved, from data parsing to report generation, in a streamlined process. See our recent poster presented at BioIT World 2018 (Boston) showing an analysis of positive allosteric modulator (PAM) drug candidates (simulated).