Around the macrolide – Impact of 3D structure of macrocycles on lipophilicity and cellular accumulation

Koštrun, Sanja; Kos, Vesna Munić; Škugor, Maja Matanović; Jakopović, Ivana Palej; Malnar, Ivica; Dragojević, Snježana; Ralić, Jovica; Alihodžić, Sulejman

doi:10.1016/j.ejmech.2017.03.056

Cited by 9 publications

(10 citation statements)

References 17 publications

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“…Inspection of the most important molecular descriptors from OPLS Model 1 (LTR_class, PEOE_VSA6, PEOE_VSA13, MolLogP, SlogP_VSA1, NHOHCount, NumHDonors) showed that they were related to various descriptions of partially charged van der Waals surface area contributions, lipophilicity, and hydrogen bonding, where the two first categories have a positive contribution with respect to accumulation, while the last category negatively influences the level of accumulation [19,20]. This is in line with previous observations that lipophilicity, hydrophobic regions, and the number of positive charges contribute positively to accumulation [15,16].…”

Section: Resultssupporting

confidence: 80%

“…Our first in silico models to predict macrocycle intracellular accumulation were 2-class decision tree models, which, apart from calculated molecular descriptors, relied on experimentally determined physicochemical properties such as lipophilicity parameter ChromlogD, or phospholipophilicity parameter CHIIAM [15]. Our later studies investigated the applicability of calculated 3D molecular descriptors with or without empirically determined lipophilicity to develop continuous prediction models for cellular accumulation [16]. Recently, we have developed a high throughput in vitro model for the indirect measurement of the cellular accumulation of compounds [17].…”

Section: Introductionmentioning

confidence: 99%

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QSAR Models for Predicting Five Levels of Cellular Accumulation of Lysosomotropic Macrocycles

Norinder

Kos

2019

IJMS

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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 (Mw > 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.

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Section: Resultssupporting

confidence: 80%

Section: Introductionmentioning

confidence: 99%

QSAR Models for Predicting Five Levels of Cellular Accumulation of Lysosomotropic Macrocycles

Norinder

Kos

2019

IJMS

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“…A comprehensive study illustrating the potential of MMFF to explore the conformational behavior of rationally designed azithromycin and clarithromycin derivatives at physiological conditions was reported by Koštrun et al [ 116 ]. Computational models based on the three-dimensional structure of macrolides were generated to explain structural, electronic, and conformational effects on measured properties and to predict the lipophilicity and cellular accumulation for this class of antibiotics from non-empirical parameters.…”

Section: Computational Simulations Of Macrolide Interactionsmentioning

confidence: 99%

Advanced Methods for Studying Structure and Interactions of Macrolide Antibiotics

Jednačak

Mikulandra

Novak

2020

IJMS

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Macrolide antibiotics are macrocyclic compounds that are clinically used and prescribed for the treatment of upper and lower respiratory tract infections. They inhibit the synthesis of bacterial proteins by reversible binding to the 23S rRNA at or near the peptidyl transferase center. However, their excellent antibacterial profile was largely compromised by the emergence of bacterial resistance. Today, fighting resistance to antibiotics is one of the greatest challenges in medicinal chemistry. Considering various physicochemical properties of macrolides, understanding their structure and interactions with macromolecular targets is crucial for the design of new antibiotics efficient against resistant pathogens. The solid-state structures of some macrolide-ribosome complexes have recently been solved, throwing new light on the macrolide binding mechanisms. On the other hand, a combination of NMR spectroscopy and molecular modeling calculations can be applied to study free and bound conformations in solution. In this article, a description of advanced physicochemical methods for elucidating the structure and interactions of macrolide antibiotics in solid state and solution will be provided, and their principal advantages and drawbacks will be discussed.

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“…In our previous work, we have used different physicochemical and 3D structural approaches to expand the chemical space of predictable structures to the area of macrocycles. 17,18 The models are mainly aimed for preselection of the compounds for the measurement of intracellular accumulation, rather than as a replacement for it.…”

Section: Introductionmentioning

confidence: 99%

“…In this project, we aimed to see whether any of the effects on cellular processes reported for some of the lysosomotropic compounds could be used in a quantitative manner to determine the intracellular accumulation and retention of these compounds in cells. We used a unique set of 47 compounds 17,18 consisting of 39 macrocycles, together with 8 nonmacrocyclic compounds, specifically designed to cover the entire feasible range of cellular accumulation intensities, as reported for pharmaceuticals so far ( Fig.1). By using the data on their intracellular accumulation and retention measured by liquid chromatography with tandem mass spectrometry (LC-MS/MS), we aimed to evaluate how well these PK parameters can be predicted from the biological endpoints related to the changes in the lysosomes.…”

Section: Introductionmentioning

confidence: 99%

Quantification of Intracellular Accumulation and Retention of Lysosomotropic Macrocyclic Compounds by High-Throughput Imaging of Lysosomal Changes

Easwaranathan

Inci

Ulrich

et al. 2019

Journal of Pharmaceutical Sciences

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Many marketed pharmaceuticals reach extremely high tissue concentrations due to accumulation in lysosomes (lysosomotropism). Quantitative prediction of intracellular concentrations of accumulating drugs is challenging, especially for macrocyclic compounds that mainly do not fit in current in silico models. We tested a unique library of 47 compounds (containing 39 macrocycles) specifically designed to cover the entire range of accumulation intensities observed with pharmaceuticals so far. For the first time, we show that intracellular concentration of compounds measured by liquid chromatography with tandem mass spectrometry correlates with the induction of phospholipidosis and inhibition of autophagy, but the highest correlation was observed with the increase of lysosomal volume (R ¼ 0.95), all measured by high-throughput imaging assays. Based only on imaging data, we developed a 5-class in vitro model for the prediction of compound accumulation with the accuracy of 81%. The measured change of total lysosomal volume can thus be used in high-throughput screening for determination of the actual intensity of intracellular accumulation of new macrocyclic compounds. The models are largely based on macrocycles, greatly improving the screening and prediction of intracellular accumulation of this challenging class. However, all tested nonmacrocyclic compounds fitted well in the models, indicating potential use of the models in broader chemical space.

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Around the macrolide – Impact of 3D structure of macrocycles on lipophilicity and cellular accumulation

Cited by 9 publications

References 17 publications

QSAR Models for Predicting Five Levels of Cellular Accumulation of Lysosomotropic Macrocycles

QSAR Models for Predicting Five Levels of Cellular Accumulation of Lysosomotropic Macrocycles

Advanced Methods for Studying Structure and Interactions of Macrolide Antibiotics

Quantification of Intracellular Accumulation and Retention of Lysosomotropic Macrocyclic Compounds by High-Throughput Imaging of Lysosomal Changes

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