Design, synthesis and biological evaluation of novel estrone phosphonates as high affinity organic anion-transporting polypeptide 2B1 (OATP2B1) inhibitors

Jójárt, Rebeka; Laczkó-Rigó, Réka; Klement, Máté; Kőhl, Gabriella; Kecskeméti, Gábor; Özvegy‐Laczka, Csilla; Mernyák, Erzsébet

doi:10.1016/j.bioorg.2021.104914

Cited by 7 publications

(4 citation statements)

References 47 publications

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“…IC 50 measurements of the six compounds that were further prioritized by our manual selection procedure (see Methods for details) are listed along with their chemical structures in Figure 2 and Table 5. Strikingly, in this selection, we could 33 Both compounds do also show a reasonable inhibitory effect on OATP1B3, however, with 18-fold (H5) and 135-fold (C7) lower affinity. Therefore, particularly, compound C7 deserves special attention when it comes to the more detailed analysis of molecular interactions.…”

Section: ■ Results and Discussionmentioning

confidence: 85%

“…Interestingly, the strongest OATP2B1 inhibitor (compound C7 , IC 50 = 40 nM) shows similar affinity to the strongest OATP2B1 inhibitor that was recently reported in the literature. 33 These findings indicate that the developed integrative modeling pipeline, combining AI-based and structure-based methods, is capable of identifying highly active compounds. Interestingly, our computational pipeline seems better suited to predict OATP2B1 inhibitors since it detected twice as many hits for OATP2B1 vs the other two transporters.…”

Section: Discussionmentioning

confidence: 90%

“…Among these, two novel OATP2B1 inhibitors were discovered ( C7 and H5 ) which show activity comparable to the highest affinity inhibitor reported in the literature– estra-1,3,5(10)-trien-17-on-2-ylphosphonate (IC 50 = 41 nM). 33 Both compounds do also show a reasonable inhibitory effect on OATP1B3, however, with 18-fold ( H5 ) and 135-fold ( C7 ) lower affinity. Therefore, particularly, compound C7 deserves special attention when it comes to the more detailed analysis of molecular interactions.…”

Section: Resultsmentioning

confidence: 95%

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Identifying Novel Inhibitors for Hepatic Organic Anion Transporting Polypeptides by Machine Learning-Based Virtual Screening

Tuerkova

Bongers

Norinder

et al. 2022

J. Chem. Inf. Model.

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Integration of statistical learning methods with structure-based modeling approaches is a contemporary strategy to identify novel lead compounds in drug discovery. Hepatic organic anion transporting polypeptides (OATP1B1, OATP1B3, and OATP2B1) are classical off-targets, and it is well recognized that their ability to interfere with a wide range of chemically unrelated drugs, environmental chemicals, or food additives can lead to unwanted adverse effects like liver toxicity and drug−drug or drug−food interactions. Therefore, the identification of novel (tool) compounds for hepatic OATPs by virtual screening approaches and subsequent experimental validation is a major asset for elucidating structure−function relationships of (related) transporters: they enhance our understanding about molecular determinants and structural aspects of hepatic OATPs driving ligand binding and selectivity. In the present study, we performed a consensus virtual screening approach by using different types of machine learning models (proteochemometric models, conformal prediction models, and XGBoost models for hepatic OATPs), followed by molecular docking of preselected hits using previously established structural models for hepatic OATPs. Screening the diverse REAL drug-like set (Enamine) shows a comparable hit rate for OATP1B1 (36% actives) and OATP1B3 (32% actives), while the hit rate for OATP2B1 was even higher (66% actives). Percentage inhibition values for 44 selected compounds were determined using dedicated in vitro assays and guided the prioritization of several highly potent novel hepatic OATP inhibitors: six (strong) OATP2B1 inhibitors (IC 50 values ranging from 0.04 to 6 μM), three OATP1B1 inhibitors (2.69 to 10 μM), and five OATP1B3 inhibitors (1.53 to 10 μM) were identified. Strikingly, two novel OATP2B1 inhibitors were uncovered (C7 and H5) which show high affinity (IC 50 values: 40 nM and 390 nM) comparable to the recently described estrone-based inhibitor (IC 50 = 41 nM). A molecularly detailed explanation for the observed differences in ligand binding to the three transporters is given by means of structural comparison of the detected binding sites and docking poses.

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Section: ■ Results and Discussionmentioning

confidence: 85%

Section: Discussionmentioning

confidence: 90%

Section: Resultsmentioning

confidence: 95%

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Identifying Novel Inhibitors for Hepatic Organic Anion Transporting Polypeptides by Machine Learning-Based Virtual Screening

Tuerkova

Bongers

Norinder

et al. 2022

J. Chem. Inf. Model.

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“…The group of 13α-estrone derivatives proved to be promising concerning their enzyme inhibitory and/or antiproliferative properties. However, their biological activity greatly depends on their structure [ 33 , 42 , 43 , 44 , 45 , 46 , 47 , 48 ]. We have observed that the substitution pattern of ring A influences bioactivity markedly.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Antiproliferative Activity of Steroidal Diaryl Ethers

et al. 2023

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Novel 13α-estrone derivatives have been synthesized via direct arylation of the phenolic hydroxy function. Chan–Lam couplings of arylboronic acids with 13α-estrone as a nucleophilic partner were carried out under copper catalysis. The antiproliferative activities of the newly synthesized diaryl ethers against a panel of human cancer cell lines (A2780, MCF-7, MDA-MB 231, HeLa, SiHa) were investigated by means of MTT assays. The quinoline derivative displayed substantial antiproliferative activity against MCF-7 and HeLa cell lines with low micromolar IC50 values. Disturbance of tubulin polymerization has been confirmed by microplate-based photometric assay. Computational calculations reveal significant interactions of the quinoline derivative with the taxoid binding site of tubulin.

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Three-component reaction between phenanthridine, acetylenic ketones and bis(polyfluoroalkyl) H-phosphonates: synthesis of E-N-acylethenyl-6-bis(polyfluoroalkyl)phosphoryl-5,6-dihydrophenanthridines

Volkov,

Khrapova,

Telezhkin

et al. 2024

Russ Chem Bull

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Design, synthesis and biological evaluation of novel estrone phosphonates as high affinity organic anion-transporting polypeptide 2B1 (OATP2B1) inhibitors

Cited by 7 publications

References 47 publications

Identifying Novel Inhibitors for Hepatic Organic Anion Transporting Polypeptides by Machine Learning-Based Virtual Screening

Identifying Novel Inhibitors for Hepatic Organic Anion Transporting Polypeptides by Machine Learning-Based Virtual Screening

Synthesis and Antiproliferative Activity of Steroidal Diaryl Ethers

Three-component reaction between phenanthridine, acetylenic ketones and bis(polyfluoroalkyl) H-phosphonates: synthesis of E-N-acylethenyl-6-bis(polyfluoroalkyl)phosphoryl-5,6-dihydrophenanthridines

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