C@PA: Computer-Aided Pattern Analysis to Predict Multitarget ABC Transporter Inhibitors

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

doi:10.1021/acs.jmedchem.0c02199

C@PA: Computer-Aided Pattern Analysis to Predict Multitarget ABC Transporter Inhibitors

J Med Chem. 2021 Mar 25;64(6):3350-3366. doi: 10.1021/acs.jmedchem.0c02199. Epub 2021 Mar 16.

Authors

Vigneshwaran Namasivayam¹, Katja Silbermann¹, Michael Wiese¹, Jens Pahnke^{2

3

4

5}, Sven Marcel Stefan^{1

2

6}

Affiliations

¹ Department of Pharmaceutical and Cellbiological Chemistry, Pharmaceutical Institute, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany.
² Department of Neuro-/Pathology, University of Oslo and Oslo University Hospital, Sognsvannsveien 20, 0372 Oslo, Norway.
³ LIED, University of Lübeck, Ratzenburger Allee 160, 23538 Lübeck, Germany.
⁴ Department of Pharmacology, Faculty of Medicine, University of Latvia, Jelgavas iela 1, 1004 Riga, Latvia.
⁵ Department of Bioorganic Chemistry, Leibniz-Institute of Plant Biochemistry, Weinberg 3, 06120 Halle, Germany.
⁶ Cancer Drug Resistance and Stem Cell Program, University of Sydney, Kolling Building, 10 Westbourne Street, Sydney, New South Wales 2065, Australia.

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors*
ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
ATP Binding Cassette Transporter, Subfamily G, Member 2 / antagonists & inhibitors*
ATP Binding Cassette Transporter, Subfamily G, Member 2 / metabolism
Animals
Dogs
Drug Design
Drug Discovery / methods*
Humans
Madin Darby Canine Kidney Cells
Models, Molecular
Multidrug Resistance-Associated Proteins / antagonists & inhibitors*
Multidrug Resistance-Associated Proteins / metabolism
Pattern Recognition, Automated / methods
Small Molecule Libraries / chemistry*
Small Molecule Libraries / pharmacology*

Substances

ATP Binding Cassette Transporter, Subfamily B, Member 1
ATP Binding Cassette Transporter, Subfamily G, Member 2
Multidrug Resistance-Associated Proteins
Small Molecule Libraries
multidrug resistance-associated protein 1