Scaffold fragmentation and substructure hopping reveal potential, robustness, and limits of computer-aided pattern analysis (C@PA)

Namasivayam, Vigneshwaran; Silbermann, Katja; Pahnke, Jens; Wiese, Michael; Stefan, Sven Marcel

doi:10.1016/j.csbj.2021.05.018

Cited by 17 publications

(28 citation statements)

References 134 publications

(347 reference statements)

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“…By comparing parental and resistant cancer cell lines using molecular biology and cellular methods, researchers have identified numerous ABC transporter substrates (21,(30)(31)(32)(33)(34) as well as inhibitors (16,(35)(36)(37)(38)(39)(40). Computational strategies were also developed to boost the modulator discovery process especially multitarget modulators (41,42). Thus, establishing new cancer cell lines that overexpresses ABC transporters, especially those with limited knowledge like MRP7, will greatly enhance our understanding of MDR in cancer.…”

Section: Discussionmentioning

confidence: 99%

Establishment and Characterization of a Novel Multidrug Resistant Human Ovarian Cancer Cell Line With Heterogenous MRP7 Overexpression

Wang

Yang

et al. 2021

Front. Oncol.

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Ovarian cancer is one of the leading female malignancies which accounts for the highest mortality rate among gynecologic cancers. Surgical cytoreduction followed by chemotherapy is the mainstay of treatment. However, patients with recurrent ovarian cancer are likely to exhibit resistance to chemotherapy due to reduced sensitivity to chemotherapeutic drugs. Adenosine triphosphate (ATP)-binding cassette (ABC) transporters have been extensively studied as multidrug resistance (MDR) mediators since they are responsible for the efflux of various anticancer drugs. Multidrug resistance protein 7 (MRP7, or ABCC10) was discovered in 2001 and revealed to transport chemotherapeutic drugs. Till now, only limited knowledge was obtained regarding its roles in ovarian cancer. In this study, we established an MRP7-overexpressing ovarian cancer cell line SKOV3/MRP7 via transfecting recombinant MRP7 plasmids. The SKOV3/MRP7 cell line was resistant to multiple anticancer drugs including paclitaxel, docetaxel, vincristine and vinorelbine with a maximum of 8-fold resistance. Biological function of MRP7 protein was further determined by efflux-accumulation assays. Additionally, MTT results showed that the drug resistance of the SKOV3/MRP7 cells was reversed by cepharanthine, a known inhibitor of MRP7. Moreover, we also found that the overexpression of MRP7 enhanced the migration and epithelial-mesenchymal transition (EMT) induction. In conclusion, we established an in vitro model of MDR in ovarian cancer and suggested MRP7 overexpression as the leading mechanism of chemoresistance in this cell line. Our results demonstrated the potential relationship between MRP7 and ovarian cancer MDR.

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Section: Discussionmentioning

confidence: 99%

Establishment and Characterization of a Novel Multidrug Resistant Human Ovarian Cancer Cell Line With Heterogenous MRP7 Overexpression

Wang

Yang

et al. 2021

Front. Oncol.

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“…The extracted substructures [ e.g ., single-standing/centered (hetero-)aromatic rings, condensed (hetero-)aromatic rings, (un)saturated side chains, extremities, and non-aromatic (hetero-)cycles, etc .] were derivatized by applying a heavy atom substitution scheme as already reported earlier 26 (scaffold fragmentation and substructure hopping). Especially the presence and positioning of (non-polar) hydrogens in the sense of a proton/non-proton pattern scheme was stressed.…”

Section: Methodsmentioning

confidence: 99%

“…On the other hand, 38, 212, and 58 dual ABCB1/ABCC1, ABCB1/ABCG2, and ABCC1/ABCG2 inhibitors are present, respectively, of which 7, 99, and 13 can be considered as potent dual ABCB1/ABCC1, ABCB1/ABCG2, and ABCC1/ABCG2 inhibitors, respectively (IC 50 < 10 µM). Finally, 187 triple ABCB1, ABCC1, and ABCG2 inhibitors can be defined, of which 54 can be considered as potent (IC 50 < 10 µM; so-called ‘Class 7’ compounds 7 , 26 , 27 ). Table 3 summarizes a survey of statistical parameters of the entire ABC_BPMDS as well as important sub-classes.…”

Section: Technical Validationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…In contrast to common molecular fingerprints for similarity-based virtual screenings 20 , 64 , the very recently reported novel drug discovery tool ‘computer-aided pattern analysis’ (‘C@PA’) identified that defined (=non-substituted) hydrogens and their positioning is particularly important in terms of the differentiation between selective and multitarget inhibition of ABC transporters 7 , 26 , 27 . Although certain fingerprints indeed consider polar hydrogens 21 , 22 , C@PA particularly discovered non-polar hydrogens with critical discriminatory potential in the virtual screening process 7 , 26 , 27 . However, the original C@PA worked with a very preliminary and limited dataset of 308 substructures which were compiled after multitarget dataset visualization and literature consideration 65 , of which only 162 substructures were active in the multitarget dataset of, at the time of the study, 1,049 compounds 27 .…”

Section: Introductionmentioning

confidence: 99%

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A curated binary pattern multitarget dataset of focused ATP-binding cassette transporter inhibitors

et al. 2022

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Multitarget datasets that correlate bioactivity landscapes of small-molecules toward different related or unrelated pharmacological targets are crucial for novel drug design and discovery. ATP-binding cassette (ABC) transporters are critical membrane-bound transport proteins that impact drug and metabolite distribution in human disease as well as disease diagnosis and therapy. Molecular-structural patterns are of the highest importance for the drug discovery process as demonstrated by the novel drug discovery tool ‘computer-aided pattern analysis’ (‘C@PA’). Here, we report a multitarget dataset of 1,167 ABC transporter inhibitors analyzed for 604 molecular substructures in a statistical binary pattern distribution scheme. This binary pattern multitarget dataset (ABC_BPMDS) can be utilized for various areas. These areas include the intended design of (i) polypharmacological agents, (ii) highly potent and selective ABC transporter-targeting agents, but also (iii) agents that avoid clearance by the focused ABC transporters [e.g., at the blood-brain barrier (BBB)]. The information provided will not only facilitate novel drug prediction and discovery of ABC transporter-targeting agents, but also drug design in general in terms of pharmacokinetics and pharmacodynamics.

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Target repurposing unravels avermectins and derivatives as novel antibiotics inhibiting energy‐coupling factor transporters (ECFTs)

Haupenthal,

Rafehi,

Kany

et al. 2024

Archiv der Pharmazie

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Energy‐coupling factor transporters (ECFTs) are membrane‐bound ATP‐binding cassette (ABC) transporters in prokaryotes that are found in pathogens against which novel antibiotics are urgently needed. To date, just 54 inhibitors of three molecular‐structural classes with mostly weak inhibitory activity are known. Target repurposing is a strategy that transfers knowledge gained from a well‐studied protein family to under‐studied targets of phylogenetic relation. Forty‐eight human ABC transporters are known that may harbor structural motifs similar to ECFTs to which particularly multitarget compounds may bind. We assessed 31 multitarget compounds which together target the entire druggable human ABC transporter proteome against ECFTs, of which nine showed inhibitory activity (hit rate 29.0%) and four demonstrated moderate to strong inhibition of an ECFT (IC50 values between 4.28 and 50.2 µM) as well as antibacterial activity against ECFT‐expressing Streptococcus pneumoniae. Here, ivermectin was the most potent candidate (MIC95: 22.8 µM), and analysis of five ivermectin derivatives revealed moxidectin as one of the most potent ECFT‐targeting antibacterial agents (IC50: 2.23 µM; MIC95: 2.91 µM). Distinct molecular‐structural features of avermectins and derivatives as well as the differential biological response of the hit compounds in general provided first indications with respect to the structure–activity relationships and mode of action, respectively.

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Scaffold fragmentation and substructure hopping reveal potential, robustness, and limits of computer-aided pattern analysis (C@PA)

Abstract: Graphical abstract

Cited by 17 publications

References 134 publications

Establishment and Characterization of a Novel Multidrug Resistant Human Ovarian Cancer Cell Line With Heterogenous MRP7 Overexpression

Establishment and Characterization of a Novel Multidrug Resistant Human Ovarian Cancer Cell Line With Heterogenous MRP7 Overexpression

A curated binary pattern multitarget dataset of focused ATP-binding cassette transporter inhibitors

Target repurposing unravels avermectins and derivatives as novel antibiotics inhibiting energy‐coupling factor transporters (ECFTs)

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