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.

Designing Soluble PROTACs: Strategies and Preliminary Guidelines

Diego García Jiménez;Matteo Rossi Sebastiano;Maura Vallaro;Elisa Moretti;Giuseppe Ermondi;Giulia Caron
2022-01-01

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 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.
2022
65
19
12639
12649
Diego García Jiménez; Matteo Rossi Sebastiano; Maura Vallaro; Valentina Mileo; Daniela Pizzirani; Elisa Moretti; Giuseppe Ermondi; Giulia Caron
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2318/1886061
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