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QSAR Models for Predicting Five Levels of Cellular Accumulation of Lysosomotropic Macrocycles
Swetox, Karolinska Institute, Unit of Toxicology Sciences, Södertälje, Sweden; Department of Computer and Systems Sciences, Stockholm University, Kista, Sweden.ORCID iD: 0000-0003-3107-331X
Swetox, Karolinska Institute, Unit of Toxicology Sciences, Södertälje, Sweden; Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden.
2019 (English)In: International Journal of Molecular Sciences, ISSN 1661-6596, E-ISSN 1422-0067, Vol. 20, no 23, article id 5938Article in journal (Refereed) Published
Abstract [en]

Drugs that accumulate in lysosomes reach very high tissue concentrations, which is evident in the high volume of distribution and often lower clearance of these compounds. Such a pharmacokinetic profile is beneficial for indications where high tissue penetration and a less frequent dosing regime is required. Here, we show how the level of lysosomotropic accumulation in cells can be predicted solely from molecular structure. To develop quantitative structure-activity relationship (QSAR) models, we used cellular accumulation data for 69 lysosomotropic macrocycles, the pharmaceutical class for which this type of prediction model is extremely valuable due to the importance of cellular accumulation for their anti-infective and anti-inflammatory applications as well as due to the fact that they are extremely difficult to model by computational methods because of their large size (M-w > 500). For the first time, we show that five levels of intracellular lysosomotropic accumulation (as measured by liquid chromatography coupled to tandem mass spectrometry-LC-MS/MS), from low/no to extremely high, can be predicted with 60% balanced accuracy solely from the compound's structure. Although largely built on macrocycles, the eight non-macrocyclic compounds that were added to the set were found to be well incorporated by the models, indicating their possible broader application. By uncovering the link between the molecular structure and cellular accumulation as the key process in tissue distribution of lysosomotropic compounds, these models are applicable for directing the drug discovery process and prioritizing the compounds for synthesis with fine-tuned accumulation properties, according to the desired pharmacokinetic profile.

Place, publisher, year, edition, pages
Basel: MDPI, 2019. Vol. 20, no 23, article id 5938
Keywords [en]
cellular accumulation, macrocycle, QSAR, OPLS, applicability domain, classification models, molecular descriptors
National Category
Biological Sciences Chemical Sciences
Identifiers
URN: urn:nbn:se:oru:diva-83151DOI: 10.3390/ijms20235938ISI: 000504428300120PubMedID: 31779113Scopus ID: 2-s2.0-85075527106OAI: oai:DiVA.org:oru-83151DiVA, id: diva2:1440467
Available from: 2020-01-15 Created: 2020-06-15 Last updated: 2022-02-10Bibliographically approved

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