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Article ; Online: Medicinal polypharmacology: Exploration and exploitation of the polypharmacolome in modern drug development.

Stefan, Sven Marcel / Rafehi, Muhammad

2023 Volume 85, Issue 1, Page(s) e22125

Abstract: At the core of complex and multifactorial human diseases, such as cancer, metabolic syndrome, or neurodegeneration, are multiple players that cross-talk in robust biological networks which are intrinsically resilient to alterations. These multifactorial ... ...

Abstract	At the core of complex and multifactorial human diseases, such as cancer, metabolic syndrome, or neurodegeneration, are multiple players that cross-talk in robust biological networks which are intrinsically resilient to alterations. These multifactorial diseases are characterized by sophisticated feedback mechanisms which manifest cellular imbalance and resistance to drug therapy. By adhering to the specificity paradigm ("one target-one drug concept"), research focused for many years on drugs with very narrow mechanisms of action. This narrow focus promoted therapy ineffectiveness and resistance. However, modern drug discovery has evolved over the last years, increasingly emphasizing integral strategies for the development of clinically effective drugs. These integral strategies include the controlled engagement of multiple targets to overcome therapy resistance. Apart from the additive or even synergistic effects in therapy, multitarget drugs harbor molecular-structural attributes to explore orphan targets of which intrinsic substrates/physiological role(s) and/or modulators are unknown for future therapy purposes. We designated this multidisciplinary and translational research field between medicinal chemistry, chemical biology, and molecular pharmacology as 'medicinal polypharmacology'. Medicinal polypharmacology emerged as alternative approach to common single-targeted pharmacology stretching from basic drug and target identification processes to clinical evaluation of multitarget drugs, and the exploration and exploitation of the 'polypharmacolome' is at the forefront of modern drug development research.
MeSH term(s)	Humans ; Polypharmacology ; Drug Discovery ; Neoplasms/drug therapy
Language	English
Publishing date	2023-11-03
Publishing country	United States
Document type	Journal Article
ZDB-ID	604587-x
ISSN	1098-2299 ; 0272-4391
ISSN (online)	1098-2299
ISSN	0272-4391
DOI	10.1002/ddr.22125
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: The big data challenge - and how polypharmacology supports the translation from pre-clinical research into clinical use against neurodegenerative diseases and beyond.

Stefan, Sven Marcel / Rafehi, Muhammad

Neural regeneration research

2023 Volume 19, Issue 8, Page(s) 1647–1648

Language	English
Publishing date	2023-11-08
Publishing country	India
Document type	Journal Article
ZDB-ID	2388460-5
ISSN	1876-7958 ; 1673-5374
ISSN (online)	1876-7958
ISSN	1673-5374
DOI	10.4103/1673-5374.387984
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Article ; Online: Multi-target ABC transporter modulators: what next and where to go?

Stefan, Sven Marcel

Future medicinal chemistry

2019 Volume 11, Issue 18, Page(s) 2353–2358

MeSH term(s)	ATP-Binding Cassette Transporters/antagonists & inhibitors ; ATP-Binding Cassette Transporters/metabolism ; Alzheimer Disease/drug therapy ; Alzheimer Disease/metabolism ; Antineoplastic Agents/chemistry ; Antineoplastic Agents/pharmacology ; Computer-Aided Design ; Humans ; Neoplasms/drug therapy ; Neoplasms/metabolism
Chemical Substances	ATP-Binding Cassette Transporters ; Antineoplastic Agents
Language	English
Publishing date	2019-09-13
Publishing country	England
Document type	Editorial
ISSN	1756-8927
ISSN (online)	1756-8927
DOI	10.4155/fmc-2019-0185
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Article: HD_BPMDS: a curated binary pattern multitarget dataset of Huntington's disease-targeting agents.

Stefan, Sven Marcel / Pahnke, Jens / Namasivayam, Vigneshwaran

Journal of cheminformatics

2023 Volume 15, Issue 1, Page(s) 109

Abstract: The discovery of both distinctive lead molecules and novel drug targets is a great challenge in drug discovery, which particularly accounts for orphan diseases. Huntington's disease (HD) is an orphan, neurodegenerative disease of which the pathology is ... ...

Abstract	The discovery of both distinctive lead molecules and novel drug targets is a great challenge in drug discovery, which particularly accounts for orphan diseases. Huntington's disease (HD) is an orphan, neurodegenerative disease of which the pathology is well-described. However, its pathophysiological background and molecular mechanisms are poorly understood. To date, only 2 drugs have been approved on the US and European markets, both of which address symptomatic aspects of this disease only. Although several hundreds of agents were described with efficacy against the HD phenotype in in vitro and/or in vivo models, a successful translation into clinical use is rarely achieved. Two major impediments are, first, the lack of awareness and understanding of the interactome-the sum of key proteins, cascades, and mediators-that contributes to HD initiation and progression; and second, the translation of the little gained knowledge into useful model systems. To counteract this lack of data awareness, we manually compiled and curated the entire modulator landscape of successfully evaluated pre-clinical small-molecule HD-targeting agents which are annotated with substructural molecular patterns, physicochemical properties, as well as drug targets, and which were linked to benchmark databases such as PubChem, ChEMBL, or UniProt. Particularly, the annotation with substructural molecular patterns expressed as binary code allowed for the generation of target-specific and -unspecific fingerprints which could be used to determine the (poly)pharmacological profile of molecular-structurally distinct molecules.
Language	English
Publishing date	2023-11-17
Publishing country	England
Document type	Journal Article
ZDB-ID	2486539-4
ISSN	1758-2946
ISSN	1758-2946
DOI	10.1186/s13321-023-00775-z
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Article ; Online: Medicinal Polypharmacology in the Clinic - Translating the Polypharmacolome into Therapeutic Benefit.

Rafehi, Muhammad / Möller, Marius / Ismail Al-Khalil, Wouroud / Stefan, Sven Marcel

Pharmaceutical research

2024 Volume 41, Issue 3, Page(s) 411–417

Abstract: Drugs with multiple targets, often annotated as 'unselective', 'promiscuous', 'multitarget', or 'polypharmacological', are widely considered in both academic and industrial research as a high risk due to the likelihood of adverse effects. However, ... ...

Abstract	Drugs with multiple targets, often annotated as 'unselective', 'promiscuous', 'multitarget', or 'polypharmacological', are widely considered in both academic and industrial research as a high risk due to the likelihood of adverse effects. However, retrospective analyses have shown that particularly approved drugs bear rich polypharmacological profiles. This raises the question whether our perception of the specificity paradigm ('one drug-one target concept') is correct - and if specifically multitarget drugs should be developed instead of being rejected. These questions provoke a paradigm shift - regarding the development of polypharmacological drugs not as a 'waste of investment', but acknowledging the existence of a 'lack of investment'. This perspective provides an insight into modern drug development highlighting latest drug candidates that have not been assessed in a broader polypharmacology-based context elsewhere embedded in a historic framework of classical and modern approved multitarget drugs. The article shall be an inspiration to the scientific community to re-consider current standards, and more, to evolve to a better understanding of polypharmacology from a challenge to an opportunity.
MeSH term(s)	Polypharmacology ; Retrospective Studies ; Drug Delivery Systems
Language	English
Publishing date	2024-02-16
Publishing country	United States
Document type	Journal Article
ZDB-ID	843063-9
ISSN	1573-904X ; 0724-8741 ; 0739-0742
ISSN (online)	1573-904X
ISSN	0724-8741 ; 0739-0742
DOI	10.1007/s11095-024-03656-8
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Article ; Online: A curated binary pattern multitarget dataset of focused ATP-binding cassette transporter inhibitors.

Stefan, Sven Marcel / Jansson, Patric Jan / Pahnke, Jens / Namasivayam, Vigneshwaran

Scientific data

2022 Volume 9, Issue 1, Page(s) 446

Abstract: 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- ... ...

Abstract	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.
MeSH term(s)	ATP-Binding Cassette Transporters/antagonists & inhibitors ; Drug Design ; Drug Discovery ; Humans ; Pharmaceutical Preparations
Chemical Substances	ATP-Binding Cassette Transporters ; Pharmaceutical Preparations
Language	English
Publishing date	2022-07-26
Publishing country	England
Document type	Dataset ; Journal Article
ZDB-ID	2775191-0
ISSN	2052-4463 ; 2052-4463
ISSN (online)	2052-4463
ISSN	2052-4463
DOI	10.1038/s41597-022-01506-z
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: The A-B-C of small-molecule ABC transport protein modulators: From inhibition to activation-a case study of multidrug resistance-associated protein 1 (ABCC1).

Wiese, Michael / Stefan, Sven Marcel

Medicinal research reviews

2019 Volume 39, Issue 6, Page(s) 2031–2081

Abstract: Several mechanisms of pharmacokinetic, metabolic, and regulatory nature have been elucidated to take part or act in concert in the phenomenon of multidrug resistance (MDR). MDR is characterized by cross-resistance of cells against chemotherapeutic agents, ...

Abstract	Several mechanisms of pharmacokinetic, metabolic, and regulatory nature have been elucidated to take part or act in concert in the phenomenon of multidrug resistance (MDR). MDR is characterized by cross-resistance of cells against chemotherapeutic agents, which are used for treatment of e.g., cancer, bacterial infections, or human immunodeficiency virus (HIV) infections. One group of proteins that combines all three stated aspects-the metabolism and distribution of drugs as well as their own regulation-is adenosine triphosphate-binding cassette (ABC) transporters. These efflux pumps use the energy of adenosine triphosphate hydrolysis for drug translocation from the membrane and the cytosol to the extracellular space, often with cotransport of a cosubstrate. Multidrug resistance-associated protein 1 (MRP1, ABCC1) had been discovered as one major key player in cancer-related MDR. The xenobiotic substrates include anthracyclines, vinca alkaloids, podophyllotoxins, as well as glutathione (GSH)-adducts of certain cytostatics. Contrary to other transport proteins involved in cancer-related MDR the activity of MRP1 is related to the GSH content of cells. A modern strategy to overcome MRP1-associated MDR is besides its inhibition the activation of GSH efflux, enforcing cell death due to cellular stress. In addition, it has recently been found that MRP1 contributes to the β-amyloid protein clearance in Alzheimer's disease (AD). Collectively, transport activation of MRP1 is of therapeutic value, and furthermore helps to elucidate the transport protein function and the mechanisms behind it. This review is meant to summarize the known concepts of MRP1 activation, which might contribute to a further understanding of MRP1 in particular and ABC transporters in general.
MeSH term(s)	ATP-Binding Cassette Transporters/metabolism ; Adenosine Triphosphatases/metabolism ; Animals ; Humans ; Multidrug Resistance-Associated Proteins/metabolism ; Protein Transport ; Xenobiotics/metabolism
Chemical Substances	ATP-Binding Cassette Transporters ; Multidrug Resistance-Associated Proteins ; Xenobiotics ; Adenosine Triphosphatases (EC 3.6.1.-) ; multidrug resistance-associated protein 1 (Y49M64GZ4Q)
Language	English
Publishing date	2019-04-03
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	603210-2
ISSN	1098-1128 ; 0198-6325
ISSN (online)	1098-1128
ISSN	0198-6325
DOI	10.1002/med.21573
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Article ; Online: Small-molecule inhibitors of multidrug resistance-associated protein 1 and related processes: A historic approach and recent advances.

Stefan, Sven Marcel / Wiese, Michael

Medicinal research reviews

2018 Volume 39, Issue 1, Page(s) 176–264

Abstract: Multidrug resistance-associated protein 1 (MRP1, ABCC1) is an ATP-binding cassette (ABC) transport protein. This efflux pump uses the energy of ATP hydrolysis to export structurally diverse antineoplastic agents in human cancers. The upregulation of MRP1 ...

Abstract	Multidrug resistance-associated protein 1 (MRP1, ABCC1) is an ATP-binding cassette (ABC) transport protein. This efflux pump uses the energy of ATP hydrolysis to export structurally diverse antineoplastic agents in human cancers. The upregulation of MRP1 (either inherent or acquired) is one major reason for the occurrence of the phenomenon called multidrug resistance (MDR). MDR is characterized by a reduced outcome of chemotherapy due to the active intracellular clearance of cytostatic drugs below the necessary effect concentration. Much effort has been made to overcome MDR, which implied high-throughput screenings of already known pharmacological and natural compounds, modification of intrinsic substrates, as well as design and synthesis of new inhibitors. This review is meant not only to summarize the most recent results over the past 10 years, but also to highlight major achievements regarding reversal of MRP1-mediated MDR, from the time of its discovery until today. The focus lies on small-molecule compounds that feature either direct MRP1 inhibition/transport blockage, toxicity against MRP1-overexpressing cells, inhibition/modification of intracellular processes necessary for MRP1 function, or modification of MRP1-related metabolic and genomic mechanisms. Considering all aspects, this review might be useful to (re)consider possible strategies to overcome MRP1-mediated MDR. Furthermore, it may be the basis for developing new, even better, highly potent, less toxic, and selective (as well as broad-spectrum) MRP1 inhibitors that will enter clinical evaluations in different malignancies and finally conduce to overcome MDR in general.
MeSH term(s)	Animals ; Biological Products/chemistry ; Biological Products/pharmacology ; Humans ; Multidrug Resistance-Associated Proteins/antagonists & inhibitors ; Multidrug Resistance-Associated Proteins/metabolism ; Pharmaceutical Preparations/chemistry ; Small Molecule Libraries/chemistry ; Small Molecule Libraries/pharmacology ; Substrate Specificity
Chemical Substances	Biological Products ; Multidrug Resistance-Associated Proteins ; Pharmaceutical Preparations ; Small Molecule Libraries ; multidrug resistance-associated protein 1 (Y49M64GZ4Q)
Language	English
Publishing date	2018-05-29
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	603210-2
ISSN	1098-1128 ; 0198-6325
ISSN (online)	1098-1128
ISSN	0198-6325
DOI	10.1002/med.21510
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Article: Binding mode analysis of ABCA7 for the prediction of novel Alzheimer's disease therapeutics.

Namasivayam, Vigneshwaran / Stefan, Katja / Pahnke, Jens / Stefan, Sven Marcel

Computational and structural biotechnology journal

2021 Volume 19, Page(s) 6490–6504

Abstract: The adenosine-triphosphate-(ATP)-binding cassette (ABC) transporter ABCA7 is a genetic risk factor for Alzheimer's disease (AD). Defective ABCA7 promotes AD development and/or progression. Unfortunately, ABCA7 belongs to the group of 'under-studied' ABC ... ...

Abstract	The adenosine-triphosphate-(ATP)-binding cassette (ABC) transporter ABCA7 is a genetic risk factor for Alzheimer's disease (AD). Defective ABCA7 promotes AD development and/or progression. Unfortunately, ABCA7 belongs to the group of 'under-studied' ABC transporters that cannot be addressed by small-molecules. However, such small-molecules would allow for the exploration of ABCA7 as pharmacological target for the development of new AD diagnostics and therapeutics. Pan-ABC transporter modulators inherit the potential to explore under-studied ABC transporters as novel pharmacological targets by potentially binding to the proposed 'multitarget binding site'. Using the recently reported cryogenic-electron microscopy (cryo-EM) structures of ABCA1 and ABCA4, a homology model of ABCA7 has been generated. A set of novel, diverse, and potent pan-ABC transporter inhibitors has been docked to this ABCA7 homology model for the discovery of the multitarget binding site. Subsequently, application of pharmacophore modelling identified the essential pharmacophore features of these compounds that may support the rational drug design of innovative diagnostics and therapeutics against AD.
Language	English
Publishing date	2021-11-27
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	2694435-2
ISSN	2001-0370
ISSN	2001-0370
DOI	10.1016/j.csbj.2021.11.035
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Article ; Online: Indole Derivatives as New Structural Class of Potent and Antiproliferative Inhibitors of Monocarboxylate Transporter 1 (MCT1; SLC16A1).

Puri, Sachin / Stefan, Katja / Khan, Sharuk L / Pahnke, Jens / Stefan, Sven Marcel / Juvale, Kapil

Journal of medicinal chemistry

2022 Volume 66, Issue 1, Page(s) 657–676

Abstract: The solute carrier (SLC) monocarboxylate transporter 1 (MCT1; SLC16A1) represents a promising target for the treatment of cancer; however, the MCT1 modulator landscape is underexplored with only roughly 100 reported compounds. To expand the knowledge ... ...

Abstract	The solute carrier (SLC) monocarboxylate transporter 1 (MCT1; SLC16A1) represents a promising target for the treatment of cancer; however, the MCT1 modulator landscape is underexplored with only roughly 100 reported compounds. To expand the knowledge about MCT1 modulation, we synthesized a library of 16 indole-based molecules and subjected these to a comprehensive biological assessment platform. All compounds showed functional inhibitory activities against MCT1 at low nanomolar concentrations and great antiproliferative activities against the MCT1-expressing cancer cell lines A-549 and MCF-7, while the compounds were selective over MCT4 (SLC16A4). Lead compound
MeSH term(s)	Molecular Docking Simulation ; Symporters/metabolism ; Antineoplastic Agents/pharmacology ; Membrane Transport Proteins ; Indoles/pharmacology ; Monocarboxylic Acid Transporters
Chemical Substances	Symporters ; Antineoplastic Agents ; Membrane Transport Proteins ; Indoles ; Monocarboxylic Acid Transporters
Language	English
Publishing date	2022-12-30
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	218133-2
ISSN	1520-4804 ; 0022-2623
ISSN (online)	1520-4804
ISSN	0022-2623
DOI	10.1021/acs.jmedchem.2c01612
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