Between Theory\nand Practice: Computational/Experimental\nIntegrated Approaches to Understand the Solubility and Lipophilicity\nof PROTACs

Emerging drug candidates more often fall in the beyond-rule-of-five\nchemical space. Among them, proteolysis targeting chimeras (PROTACs)\nhave gained great attention in the past decade. Although physicochemical\nproperties of small molecules accomplishing Lipinski’s rule-of-five\ncan now be easily predicted through models generated by large data\ncollections, for PROTACs the knowledge is still limited and heterogeneous,\nhampering their prediction. Here, the kinetic solubility and the coefficient\nof distribution at pH 7.4 (LogD<sub>7.4</sub>) of 44 PROTACs, designed\nand synthesized to cover a wide chemical space, were measured. Their\ngenerally low solubility and high lipophilicity required an optimization\nof the experimental methods. Concerning the LogD<sub>7.4</sub>, several <i>in silico</i> prediction tools were tested, which were quite\naccurate for classical small molecules but provided dissimilar outcomes\nfor PROTACs. Finally, <i>in silico</i> models for the prediction\nof PROTACs’ kinetic solubility and LogD<sub>7.4</sub> were\nproposed by combining in-house generated experimental data with 3D\ndescription of PROTACs’ structures.