Current Advances in Studying Clinically Relevant Transporters of the Solute Carrier (SLC) Family by Connecting Computational Modeling and Data Science

Türková, Alžběta; Zdrazil, Barbara

doi:10.1016/j.csbj.2019.03.002

Cited by 19 publications

(16 citation statements)

References 140 publications

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“…Deacetylated oligomers reveal higher lipophilicity and hydrogen bonding potential that may conduct to their inhibitory effect against OATP1B1 too. Furthermore, the role of computational methods in predicting clinically relevant transporter interactions has been recognized (Türková and Zdrazil, 2019).…”

Section: Discussionmentioning

confidence: 99%

Computational Assessment of the Pharmacological Profiles of Degradation Products of Chitosan

Roman

Som

et al. 2019

Front. Bioeng. Biotechnol.

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Chitosan is a natural polymer revealing an increased potential to be used in different biomedical applications, including drug delivery systems, and tissue engineering. It implies the evaluation of the organism response to the biomaterial implantation. Low-molecular degradation products, the chito-oligomers, are resulting mainly from the influence of enzymes, which are found in the organism fluids. Within this study, we have performed the computational assessment of pharmacological profiles and toxicological effects on human health of small chito-oligomers with distinct molecular weights, deacetylation degrees, and acetylation patterns. Our approach is based on the fact that regulatory agencies and researchers in the drug development field rely on the use of modeling to predict biological effects and to guide decision making. To be considered as valid for regulatory purposes, every model that is used for predictions should be associated with a defined toxicological endpoint and has appropriate robustness and predictivity. Within this context, we have used FAF-Drugs4, SwissADME, and PreADMET tools to predict the oral bioavailability of chito-oligomers and SwissADME, PreADMET, and admetSAR2.0 tools to predict their pharmacokinetic profiles. The organs and genomic toxicities have been assessed using admetSAR2.0 and PreADMET tools but specific computational facilities have been also used for predicting different toxicological endpoints: Pred-Skin for skin sensitization, CarcinoPred-EL for carcinogenicity, Pred-hERG for cardiotoxicity, ENDOCRINE DISRUPTOME for endocrine disruption potential and Toxtree for carcinogenicity and mutagenicity. Our computational assessment showed that investigated chito-oligomers reflect promising pharmacological profiles and limited toxicological effects on humans, regardless of molecular weight, deacetylation degree, and acetylation pattern. According to our results, there is a possible inhibition of the organic anion transporting peptides OATP1B1 and/or OATP1B3, a weak potential of cardiotoxicity, a minor probability of affecting the androgen receptor, and phospholipidosis. Consequently, these results may be used to guide or to complement the existing in vitro and in vivo toxicity tests, to optimize biomaterials properties and to contribute to the selection of prototypes for nanocarriers.

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Section: Discussionmentioning

confidence: 99%

Computational Assessment of the Pharmacological Profiles of Degradation Products of Chitosan

Roman

Som

et al. 2019

Front. Bioeng. Biotechnol.

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“…An in-house data set of new 13α-estrone derivatives with measured IC 50 values on OATP1B1, OATP1B3, and OATP2B1 has been used in order to augment the compound data set from public sources with compounds showing a tendency toward higher affinity for OATP2B1 (which is to date the least studied transporter of the three hepatic OATPs). 31 A special focus of the developed pipeline is ensemble docking. Inclusion of protein conformational flexibility is expected to increase confidence of the applicability of the structural models for docking.…”

Section: Introductionmentioning

confidence: 99%

Data-Driven Ensemble Docking to Map Molecular Interactions of Steroid Analogs with Hepatic Organic Anion Transporting Polypeptides

Tuerkova

Ungvári

Laczkó-Rigó

et al. 2021

J. Chem. Inf. Model.

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Hepatic organic anion transporting polypeptides—OATP1B1, OATP1B3, and OATP2B1—are expressed at the basolateral membrane of hepatocytes, being responsible for the uptake of a wide range of natural substrates and structurally unrelated pharmaceuticals. Impaired function of hepatic OATPs has been linked to clinically relevant drug–drug interactions leading to altered pharmacokinetics of administered drugs. Therefore, understanding the commonalities and differences across the three transporters represents useful knowledge to guide the drug discovery process at an early stage. Unfortunately, such efforts remain challenging because of the lack of experimentally resolved protein structures for any member of the OATP family. In this study, we established a rigorous computational protocol to generate and validate structural models for hepatic OATPs. The multistep procedure is based on the systematic exploration of available protein structures with shared protein folding using normal-mode analysis, the calculation of multiple template backbones from elastic network models, the utilization of multiple template conformations to generate OATP structural models with various degrees of conformational flexibility, and the prioritization of models on the basis of enrichment docking. We employed the resulting OATP models of OATP1B1, OATP1B3, and OATP2B1 to elucidate binding modes of steroid analogs in the three transporters. Steroid conjugates have been recognized as endogenous substrates of these transporters. Thus, investigating this data set delivers insights into mechanisms of substrate recognition. In silico predictions were complemented with in vitro studies measuring the bioactivity of a compound set on OATP expressing cell lines. Important structural determinants conferring shared and distinct binding patterns of steroid analogs in the three transporters have been identified. Overall, this comparative study provides novel insights into hepatic OATP-ligand interactions and selectivity. Furthermore, the integrative computational workflow for structure-based modeling can be leveraged for other pharmaceutical targets of interest.

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“…They are distributed in many tissues, but mainly act in the kidney (25). In the kidney, they are expressed in the basal lateral membrane of renal tubular epithelial cells (26,27), which promote the uptake of MTX from blood into renal tubular epithelial cells and mediate the urine excretion of MTX (28,29). Previous studies have shown that puerarin can inhibit the renal excretion of MTX by inhibiting the expression of OAT1/3, resulting in increased plasma MTX level (7).…”

Section: Discussionmentioning

confidence: 99%

“…The efflux transporter P-gp belongs to the adenosine triphosphate (ATP)-binding cassette transporter family (ABC) (27). It is mainly distributed in the small intestine and affects the reabsorption of MTX in the intestine (30,31).…”

Section: Discussionmentioning

confidence: 99%

Wuzhi capsule increased systemic exposure to methotrexate by inhibiting the expression of OAT1/3 and P-gp

Fu¹,

Wang²,

Guo³

et al. 2021

Ann Transl Med

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Background: Methotrexate (MTX) is an important anticancer agent and immunosuppressant with a narrow therapeutic window. Wuzhi capsule (WZC) is an extract of Schisandra which is widely used to treat liver diseases. Co-administration of MTX and WZC is common in the clinical setting, but research on the interaction between WZC and MTX is limited. This study aimed to investigate the effects of WZC on the pharmacokinetics of MTX in rats and to explore the role of membrane transport proteins OAT1/3 and P-gp in the interaction of these drugs.Methods: Plasma MTX concentration was detected by ultra-performance liquid chromatography-tandem mass spectrometer (UPLC-MS/MS), and the messenger RNA (mRNA) and protein expression of OAT1/3 and P-gp was evaluated by reverse transcription quantitative polymerase chain reaction (RT-qPCR) and western blotting analyses, respectively. Results:The study results revealed that co-administration of WZC decreased the CL z/F and V z/F of MTX, increased the C max and area under the curve [(AUC) 0-24 h ] of MTX, and inhibited OAT1/3 expression in the kidney and P-gp expression in the small intestine. Conclusions:The findings suggested that there is a drug interaction between WZC and MTX and that OAT1/3 in the kidney and P-gp in the small intestine may be the main targets mediating the drug interaction, and attention should be paid when they are used in combination.

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Current Advances in Studying Clinically Relevant Transporters of the Solute Carrier (SLC) Family by Connecting Computational Modeling and Data Science

Cited by 19 publications

References 140 publications

Computational Assessment of the Pharmacological Profiles of Degradation Products of Chitosan

Computational Assessment of the Pharmacological Profiles of Degradation Products of Chitosan

Data-Driven Ensemble Docking to Map Molecular Interactions of Steroid Analogs with Hepatic Organic Anion Transporting Polypeptides

Wuzhi capsule increased systemic exposure to methotrexate by inhibiting the expression of OAT1/3 and P-gp

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