Between Theory and Practice: Computational/Experimental Integrated Approaches to Understand the Solubility and Lipophilicity of PROTACs

Emerging drug candidates more often fall in the beyond-rule-of-five
chemical space. Among them, proteolysis targeting chimeras (PROTACs)
have gained great attention in the past decade. Although physicochemical
properties of small molecules accomplishing Lipinski’s rule-of-five
can now be easily predicted through models generated by large data
collections, for PROTACs the knowledge is still limited and heterogeneous,
hampering their prediction. Here, the kinetic solubility and the coefficient
of distribution at pH 7.4 (LogD7.4) of 44 PROTACs, designed
and synthesized to cover a wide chemical space, were measured. Their
generally low solubility and high lipophilicity required an optimization
of the experimental methods. Concerning the LogD7.4, several in silico prediction tools were tested, which were quite
accurate for classical small molecules but provided dissimilar outcomes
for PROTACs. Finally, in silico models for the prediction
of PROTACs’ kinetic solubility and LogD7.4 were
proposed by combining in-house generated experimental data with 3D
description of PROTACs’ structures.