Designing Soluble PROTACs: Strategies and Preliminary Guidelines.

ABSTRACT: Solubility optimization is a crucial step to obtaining oral PROTACs. Here we measured the thermodynamic solubilities (log S) of 21 commercial PROTACs. Next, we measured BRlogD and log k_w^IAM (lipophilicity), EPSA, and Δ log k_w^IAM (polarity) and showed that lipophilicity plays a major role in governing log S, but a contribution of polarity cannot be neglected. Two-/three-dimensional descriptors calculated on conformers arising from conformational sampling and steered molecular dynamics failed in modeling solubility. Infographic tools were used to identify a privileged region of soluble PROTACs in a chemical space defined by BRlogD, log k_w^IAM and topological polar surface area, while machine l

SUBMITTER: Garcia Jimenez D 

PROVIDER: S-EPMC9574862 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature