Based on literature
reports of the last two decades, a computer-aided
pattern analysis (C@PA) was implemented for the discovery of novel
multitarget ABCB1 (P-gp), ABCC1 (MRP1), and ABCG2 (BCRP) inhibitors.
C@PA included basic scaffold identification, substructure search and
statistical distribution, as well as novel scaffold extraction to
screen a large virtual compound library. Over 45,000 putative and
novel broad-spectrum ABC transporter inhibitors were identified, from
which 23 were purchased for biological evaluation. Our investigations
revealed five novel lead molecules as triple ABCB1, ABCC1, and ABCG2
inhibitors. C@PA is the very first successful computational approach
for the discovery of promiscuous ABC transporter inhibitors.
A virtual screening protocol with
combination of similarity search
and pharmacophore modeling was applied to virtually screen a large
compound library to gain new scaffolds regarding ABCC1 inhibition.
Biological investigation of promising candidates revealed four compounds
as ABCC1 inhibitors, three of them with scaffolds not associated with
ABCC1 inhibition until now. The best hit moleculea thienopyrimidinewas
a moderately potent, competitive inhibitor of the ABCC1-mediated transport
of calcein AM which also sensitized ABCC1-overexpressing cells toward
daunorubicin. Further evaluation showed that it was a moderately potent,
competitive inhibitor of the ABCB1-mediated transport of calcein AM,
and noncompetitive inhibitor of the ABCG2-mediated pheophorbide A
transport. In addition, the thienopyrimidine could also sensitize
ABCB1- as well as ABCG2-overexpressing cells toward daunorubicin and
SN-38, respectively, in concentration ranges that qualified it as
one of the ten best triple ABCC1/ABCB1/ABCG2 inhibitors in the literature.
Besides, three more new multitarget inhibitors were identified by
this virtual screening approach.
In the search for highly effective modulators addressing ABCG2mediated MDR, 23 pyrimidines were synthesized and biologically assessed. Seven derivatives with (a) nitrogen-and/or halogen-containing residue(s) had extraordinary potencies against ABCG2 (IC 50 < 150 nM). The compounds competitively inhibited ABCG2-mediated Hoechst 33342 transport but were not substrates of ABCG2. The most potent MDR reverser, compound 19, concentration-dependently increased SN-38-mediated cancer cell death at 11 nM (EC 50 ), time-dependently doubled SN-38 toxicity in a period of 7 days at 10 nM, and half-maximally accelerated cell death combined with SN-38 at 17 nM. No induction of ABCG2 was observed. Furthermore, 11 pyrimidines were revealed as triple ABCB1/ABCC1/ABCG2 inhibitors. Five possessed IC 50 values below 10 μM against each transporter, classifying them as some of the 50 most potent multitarget ABC transporter inhibitors. The most promising representative, compound 37, reversed ABCB1-, ABCC1-, and ABCG2-mediated MDR, making it one of the three most potent ABC transporter inhibitors and reversers of ABC transporters-mediated MDR.
Motivation
Multitargeting features of small-molecules have been of increasing interest in recent years. Polypharmacological drugs that address several therapeutic targets may provide greater therapeutic benefits for patients. Furthermore, multitarget compounds can be used to address proteins of the same (or similar) protein families for their exploration as potential pharmacological targets. In addition, the knowledge of multitargeting features is of major importance in the drug selection process; particularly in ultra-large virtual screening procedures to gain high-quality compound collections. However, large-scale multitarget modulator landscapes are almost non-existent.
Results
We implemented a specific feature-driven computer-aided pattern analysis (C@PA) to extract molecular-structural features of inhibitors of the model protein family of ATP-binding cassette (ABC) transporters. New molecular-structural features have been identified that successfully expanded the known multitarget modulator landscape of pan-ABC transporter inhibitors. The prediction capability was biologically confirmed by the successful discovery of pan-ABC transporter inhibitors with a distinct inhibitory activity profile.
Availability and implementation
The multitarget dataset is available under the http://www.panabc.info URL and its use is free of charge.
Supplementary information
Supplementary data is available at Bioinformatics online.
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