A general model for predicting the binding affinity of reversibly and irreversibly dimerized ligands

PLoS One. 2017 Nov 22;12(11):e0188134. doi: 10.1371/journal.pone.0188134. eCollection 2017.

Abstract

Empirical data has shown that bivalent inhibitors can bind a given target protein significantly better than their monomeric counterparts. However, predicting the corresponding theoretical fold improvements has been challenging. The current work builds off the reacted-site probability approach to provide a straightforward baseline reference model for predicting fold-improvements in effective affinity of dimerized ligands over their monomeric counterparts. For the more familiar irreversibly linked bivalents, the model predicts a weak dependence on tether length and a scaling of the effective affinity with the 3/2 power of the monomer's affinity. For the previously untreated case of the emerging technology of reversibly linking dimers, the effective affinity is also significantly improved over the affinity of the non-dimerizing monomers. The model is related back to experimental quantities, such as EC50s, and the approaches to fully characterize the system given the assumptions of the model. Because of the predicted significant potency gains, both irreversibly and reversibly linked bivalent ligands offer the potential to be a disruptive technology in pharmaceutical research.

MeSH terms

  • Binding Sites
  • Dimerization*
  • Ligands
  • Models, Molecular*

Substances

  • Ligands

Grants and funding

KWF was employed at BlinkBio, Inc. and performed this work as part of his regular employment responsibilities. Funders provided useful scientific feedback on the prepared manuscript and decided when the final product could be released. The funder provided support in the form of salaries for author KWF, but did not have any additional role in the study design, data collection and analysis, decision to publish (beyond timing of release), or preparation of the manuscript (except for scientific discussions, as acknowledged in the acknowledgments). The specific roles of all authors are articulated in the ‘author contributions’ section.