Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 65, Issue 19, Pages 12639-12649Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.2c00201
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Funding
- CRT Foundation
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Solubility optimization is crucial for obtaining oral PROTACs. Lipophilicity plays a major role in governing solubility, but the contribution of polarity cannot be neglected. By using infographic tools and machine learning, a privileged region for soluble PROTACs was identified, providing promising guidelines for optimizing PROTAC solubility.
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 delta 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 -/threedimensional 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 learning provided a log S classification model. Finally, for three pairs of PROTACs we measured the solubility, lipophilicity, and polarity of the building blocks and identified the limits of estimating PROTAC solubility from the synthetic components. Overall, this paper provides promising guidelines for optimizing PROTAC solubility in early drug discovery programs.
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