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

Kenneth W Foreman,Jose M G Vilar

doi:10.1371/journal.pone.0188134

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.

Highlights

The basis for expecting success in targeted pharmacological therapies has implicitly rested on the assumption of the existence of a relatively small, well-defined pocket to which a molecule with “drug-like” properties can bind
The reacted-site probability approach ignores the potential influence of tethers on the probability of monomers from the same bivalent ligand binding to the same target when it contains dual binding sites
We have developed computational models to describe the thermodynamics of reversibly and irreversibly tethered homodimeric molecules binding to targets with dual binding sites

Summary

Introduction

The basis for expecting success in targeted pharmacological therapies has implicitly rested on the assumption of the existence of a relatively small, well-defined pocket to which a molecule with “drug-like” properties can bind. We build on the reacted-site probability approach to describe the scenario in which two identical non-interacting ligands bind two separate sites while including a distance-dependent model for both irreversibly and reversibly dimerized monomers. Ρs c) Fraction of total target molecules which have both sites occupied by a single bivalent ligand (FT,Dim) as a function of tether length and dissociation constant for the monovalent ligand (KD) from Eq 28.

Results

Conclusion