Journal
COMPUTATIONAL AND STRUCTURAL BIOTECHNOLOGY JOURNAL
Volume 19, Issue -, Pages 3269-3283Publisher
ELSEVIER
DOI: 10.1016/j.csbj.2021.05.018
Keywords
Well-studied ABC transporters; ABCB1 (P-gp); ABCC1 (MRP1); ABCG2 (BCRP); Under-studied ABC transporters (e.g. ABCA7); Triple / multitarget / broad-spectrum / promiscuous inhibitor / antagonist; Pan-ABC inhibition / antagonism / blockage (PANABC); Pattern analysis (C@PA); Multitarget fingerprints; Alzheimer's disease (AD); Multidrug resistance (MDR)
Funding
- Deutsche Forschungsgemeinschaft (DFG
- German Research Foundation)/Germany [DFG 263024513]
- EFRE und Ministerium fur Wirtschaft, Wissenschaft und Digitalisierung achsen-Anhalt/Germany [ZS/2016/05/78617]
- Latvian Council of Science/Latvia [lzp-2018/1-0275]
- Nasjonalforeningen [16154]
- HelseSO/Norway [2016062, 2019054, 2019055]
- Barnekreftforeningen [19008]
- EEA grant/Norway grants Kappa programme [TAC. R TARIMAD TO100078]
- Norges forskningsradet/Norway [251290, 260786 PROP-AD, 295910 NAPI, 327571 PETABC]
- European Commission [643417]
- AKA [301228]
- BMBF [01ED1605]
- CSO-MOH [30000-12631]
- NFR [260786, 327571]
- SRC [2015-06795, 2020-02905]
- FFG [882717]
- MSMT [8F21002]
- VIAA [ES RTD/2020/26]
- ANR [20-JPW2-000204]
- European Union [643417]
- DFG [446812474]
- Academy of Finland (AKA) [301228] Funding Source: Academy of Finland (AKA)
Ask authors/readers for more resources
C@PA is a powerful tool for predicting multitarget ABC transporter inhibitors by analyzing molecular features statistically. The method can elucidate positive and negative patterns by analyzing a fixed set of small molecules.
Computer-aided pattern analysis (C@PA) was recently presented as a powerful tool to predict multitarget ABC transporter inhibitors. The backbone of this computational methodology was the statistical analysis of frequently occurring molecular features amongst a fixed set of reported small-molecules that had been evaluated toward ABCB1, ABCC1, and ABCG2. As a result, negative and positive patterns were elucidated, and secondary positive substructures could be suggested that complemented the multitarget fingerprints. Elevating C@PA to a non-statistical and exploratory level, the concluded secondary positive patterns were extended with potential positive substructures to improve C@PA's prediction capabilities and to explore its robustness. A small-set compound library of known ABCC1 inhibitors with a known hit rate for triple ABCB1, ABCC1, and ABCG2 inhibition was taken to virtually screen for the extended positive patterns. In total, 846 potential broad-spectrum ABCB1, ABCC1, and ABCG2 inhibitors resulted, from which 10 have been purchased and biologically evaluated. Our approach revealed 4 novel multitarget ABCB1, ABCC1, and ABCG2 inhibitors with a biological hit rate of 40%, but with a slightly lower inhibitory power than derived from the original C@PA. This is the very first report about discovering novel broadspectrum inhibitors against the most prominent ABC transporters by improving C@PA. (C) 2021 The Author(s). Published by Elsevier B.V. on behalf of Research Network of Computational and Structural Biotechnology.
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