Through the long, and on-going, journey of developing predictive methods to construct ligand-receptor binding models, most often to estimate IC50 values in the format of QSAR models, contributions from the receptor have been neglected. Receptor information was, in the beginning, simply not available. These days, while much ligand-receptor information is available, an overarching paradigm which permits the joining of totally equivalent and comparative receptor-independent [RI] and receptor-dependent [RD] modeling methods does not exist. Simply put, we cannot 'subtract' an RD model from an equivalent RI model to answer that most hidden, but also most worrisome question, " how much crucial design information is lost when being limited to performing only an RI analysis. The paradigm of 4D-QSAR analysis does appear to afford identical and comparative model development capabilities for both RI and RD studies. As such, both numeric and actual spatial pharmacophore substractions of RI and RD QSAR models developed from training sets in which receptor information is available can be performed. Consequently, a general assessment of lost design information in an RI study can be made. However, there does appear to be only limited qualitiative, but yet interesting general trends, regarding the particular display of design information loss or mis-representation in RI models. On a brighter note, differences in receptor geometry, as well as unearthing of coupling of receptor units motions between 'tight' and 'loose' ligand binders over the course of MD simulations integral to the RD-QSAR study may provide an additional 'dimension' to explore as part of the benefit to performing a RD-4D-QSAR study.

Paradigm which permits the parsing of information content arising from receptor-independent ligand activity models and receptor-dependent activity models

250th National Meeting (2015)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.