Discovery solubility measurement and assessment of small molecules with drug development in mind

Barrett, Jaclyn A.; Yang, Wenzhan; Skolnik, Suzanne; Belliveau, Lisa M; Patros, Kellyn M

doi:10.1016/j.drudis.2022.01.017

Cited by 39 publications

(24 citation statements)

References 49 publications

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“…In the pharmaceutical industry the type of solubility measurements is driven by the stage of the project, with kinetic solubility being the preferred method in early drug discovery . Its measurement only requires an initial DMSO stock solution which is precipitated by the addition of an aqueous phase. , Here, we measured thermodynamic solubility, often determined in late lead optimization, which efficiently considers the solubility value when the equilibrium with the stable phase or polymorph has been reached.…”

Section: Resultsmentioning

confidence: 99%

Designing Soluble PROTACs: Strategies and Preliminary Guidelines

et al. 2022

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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 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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Section: Resultsmentioning

confidence: 99%

Designing Soluble PROTACs: Strategies and Preliminary Guidelines

et al. 2022

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“…Aqueous solubility is a key physicochemical attribute required for the characterization of an active pharmaceutical ingredient during drug discovery and development. A drug molecule needs to be sufficiently soluble to quantitate meaningful activities in in vitro assays as well as to achieve adequate absorption for safety and efficacy evaluation in preclinical models and clinical trials . Hydrophilic payloads could facilitate their conjugation to the antibody in aqueous buffers and increase the solubility of antibody drug conjugates to improve their pharmacokinetics .…”

Section: Introductionmentioning

confidence: 99%

“…A drug molecule needs to be sufficiently soluble to quantitate meaningful activities in in vitro assays as well as to achieve adequate absorption for safety and efficacy evaluation in preclinical models and clinical trials. 1 Hydrophilic payloads could facilitate their conjugation to the antibody in aqueous buffers and increase the solubility of antibody drug conjugates to improve their pharmacokinetics. 2 High throughput solubility measurements have been developed for quick determination of kinetic and thermodynamic (equilibrium) solubility.…”

Section: ■ Introductionmentioning

confidence: 99%

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Building Machine Learning Small Molecule Melting Points and Solubility Models Using CCDC Melting Points Dataset

Zhu

Polyakov

Bajjuri

et al. 2023

J. Chem. Inf. Model.

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Predicting solubility of small molecules is a very difficult undertaking due to the lack of reliable and consistent experimental solubility data. It is well known that for a molecule in a crystal lattice to be dissolved, it must, first, dissociate from the lattice and then, second, be solvated. The melting point of a compound is proportional to the lattice energy, and the octanol−water partition coefficient (log P) is a measure of the compound's solvation efficiency. The CCDC's melting point dataset of almost one hundred thousand compounds was utilized to create widely applicable machine learning models of small molecule melting points. Using the general solubility equation, the aqueous thermodynamic solubilities of the same compounds can be predicted. The global model could be easily localized by adding additional melting point measurements for a chemical series of interest.

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“…The pharmaceutical industry has acknowledged the importance of solubility expertise over many years [ 20 , 21 ]. The solubility profile of pharmaceuticals, in particular in the field of drug research and development, offers valuable information for enhancing the quality of drug candidates and raises the success rate in a clinic by assisting pharmacists in making knowledgeable judgments [ 22 ]. Furthermore, solubility data is useful for estimating in vivo pharmacokinetics, which improves dose prediction [ 23 ].…”

Section: Introductionmentioning

confidence: 99%

Solubility and Thermodynamic Properties of Febuxostat in Various (PEG 400 + Water) Mixtures

et al. 2022

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The solubility of the poorly soluble medicine febuxostat (FXT) (3) in various {polyethylene glycol 400 (PEG 400) (1) + water (H2O) (2)} mixtures has been examined at 298.2–318.2 K and 101.1 kPa. FXT solubility was measured using an isothermal method and correlated with “van’t Hoff, Apelblat, Buchowski–Ksiazczak λh, Yalkowsky–Roseman, Jouyban–Acree, and Jouyban–Acree-van’t Hoff models”. FXT mole fraction solubility was enhanced via an increase in temperature and PEG 400 mass fraction in {(PEG 400 (1) + H2O (2)} mixtures. Neat PEG 400 showed the highest mole fraction solubility of FXT (3.11 × 10–2 at 318.2 K), while neat H2O had the lowest (1.91 × 10–7 at 298.2 K). The overall error value was less than 6.0 % for each computational model, indicating good correlations. Based on the positive values of apparent standard enthalpies (46.72–70.30 kJ mol−1) and apparent standard entropies (106.4–118.5 J mol−1 K−1), the dissolution of FXT was “endothermic and entropy-driven” in all {PEG 400 (1) + H2O (2)} mixtures examined. The main mechanism for FXT solvation in {PEG 400 (1) + H2O (2)} mixtures was discovered to be an enthalpy-driven process. In comparison to FXT-H2O, FXT-PEG 400 showed the strongest molecular interactions. In conclusion, these results suggested that PEG 400 has considerable potential for solubilizing a poorly soluble FXT in H2O.

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Discovery solubility measurement and assessment of small molecules with drug development in mind

Cited by 39 publications

References 49 publications

Designing Soluble PROTACs: Strategies and Preliminary Guidelines

Designing Soluble PROTACs: Strategies and Preliminary Guidelines

Building Machine Learning Small Molecule Melting Points and Solubility Models Using CCDC Melting Points Dataset

Solubility and Thermodynamic Properties of Febuxostat in Various (PEG 400 + Water) Mixtures

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