The Necessity for Polypharmacological Research – An Editorial on ‘Network Polypharmacology of ATP-binding Cassette (ABC) and Solute Carrier (SLC) Transporters’ DOI Creative Commons
Muhammad Rafehi, Kapil Juvale, Łukasz Pułaski

et al.

Frontiers in Pharmacology, Journal Year: 2025, Volume and Issue: 16

Published: March 21, 2025

Polypharmacology is widely perceived as promiscuity of drugs, i.e., their propensity to address off-targets and thereby cause adverse effects. Multitargeticity drugs usually undesired, thus, mostly inappropriately assessed, described, reported [1]. The lack research in this field stands the way a deeper understanding polypharmacology -and tremendous potential for therapy it bears. This Research Topic was edited by researchers working highlight important aspects on multiple levels, with focus membrane transporters prototypical protein group.A clear precise language fundamental concept polypharmacology. Stefan Rafehi thus provided first-in-field glossary describing relevant terminology within broader context drug discovery development [2]. interconnection used different areas supports interdisciplinary collaboration, which essential broad-scale assessments bioactivities characterize drugs. Thus, providing guideline use correct inclusive language, offer framework sustainable collaborative large-scale assessment platforms, sharing data, high-quality output.The conceptualization, development, validation new platforms identify validate novel targets requires repertoire tools. Here, Song, Zhang, Fu, coworkers described an easily applicable transferable LC-MS/MS-based workflow transporter function [3]. properties accurate description interpretation safety.The depends several factors, e.g., stereoselectivity toward chiral like verapamil, that bridge concepts stereoselectivity. Also, distribution chemical patterns [4][5][6][7] resultant physicochemistry [8] determine interactions various targets. On other hand, tendency certain accept ligands (i.e., polyspecificity) structural specificities, polymorphisms or (drug-selected) mutations, may be basis cross-resistance failure case efflux transporters. Gupta analyzed polyspecific frequently occurring mutations impact binding [9]. As turned out, polypharmacological substrates ('polysubstrates'), mitoxantrone, critically influenced key -suggesting existence 'backbone amino acids' constitute polyspecificity 'multitarget sites') [10,11].Concerning commonalities proteins are otherwise functionally phylogenetically distant from each other, 'translation between species' understand differences species project knowledge useful applications. Luckenbach Burkhardt-Medicke emphasized topic studying human zebrafish transporters, revealing operational temperature needs vary due homoio-and poikilotherm nature respective organisms [12]. However, although (related) work at conditions, polypharmacologicals such verapamil still exert findings contribute better polypharmacology.The regulation expression genetic changes. It could not only themselves, but also change pharmacology altered target modifier expression. Puris colleagues have focused female male mice applying polyanalytical approaches [13]. Sex inequality medical its relevance -is regularly neglected issue bears particular disease treatment equality public health services advanced therapies.In context, polypharmacy, has solid standing both classical pharmacotherapy traditional Chinese medicine. particularly true considering network multitarget ability variety structurally, functionally, and/or proteins, ion channels, kinases. Wang, Li, addressed aspect identifying bioactive constituents herbal formula, Qingdu Fang, bioinformatic [14].Amongst identified active ingredients quercetin, flavonoid known very rich -above all regarding -that indeed represents template addressing networks.Despite potential, disregarded independent (and important) field:(i) being actively denied purposes, claiming academic commercial focusing strategy improve therapeutic benefit. certainly untrue many (a) despite specificity [e.g., tyrosine kinase inhibitors (TKIs) central nervous system (CNS) drugs], (b) re-purposed tackle prevalent orphan diseases (e.g., acetylsalicylic acid, minoxidil, sildenafil, thalidomide, etc.), (c) intentionally developed engage tirzepatide), (d) combination therapy; collectively cancer, HIV infection, tuberculosis, etc.) [15];(ii) argued 'specificity key'. any ultimately prevent) improving safety discouraged, eventually resulting opposite: insufficiently characterized, less safe drugs;(iii) initially discovered deliberately designed bear affinities desired potentially undesired) either too similar leading off-target effects events. necessary optimize balance activities, support endorsement scientific communities;(iv) indeed, repurposing programs tedious, initial screenings against panel necessary. supporting programs, global whole strengthened, allowing local grow expertise rather than acquiring single (financially well-equipped) laboratory would undermine efforts green science, sustainability, research;(v) thorough provide druggability yet undruggable [16]. possibilities arrangement acids limited common motifs been earlier 'superfolds', 'supersites', [10,11], ('privileged ligands') specific entities showing activities distinct represent valuable tools [4][5][6][7][8]. since screening compounds most cases low potency, believe there no interest weak starting points further hit-to-lead optimization. Nevertheless, previous studies shown result potent promising hit molecules [17]. And even if activity favorable: one point always none;(vi) 'undruggability' newly often denied. claimed some surrogate target, issues assay resources effort communities -thereby questioning need privileged all. specifically these reasons can justify ligands: Undoubtedly, medicinal chemistry currently unable serve fields explore 'undruggable' Once properly identified, reported, inexpensive, accessible, enrich pool methodologies life sciences.In conclusion, matters -be designing There much more just 'dirty drugs', 'frequent hitters', 'bad actors' 'nuisance compounds' -it about risks. All contributors puzzle pieces our collective beneficial, safe,

Language: Английский

The Necessity for Polypharmacological Research – An Editorial on ‘Network Polypharmacology of ATP-binding Cassette (ABC) and Solute Carrier (SLC) Transporters’ DOI Creative Commons
Muhammad Rafehi, Kapil Juvale, Łukasz Pułaski

et al.

Frontiers in Pharmacology, Journal Year: 2025, Volume and Issue: 16

Published: March 21, 2025

Polypharmacology is widely perceived as promiscuity of drugs, i.e., their propensity to address off-targets and thereby cause adverse effects. Multitargeticity drugs usually undesired, thus, mostly inappropriately assessed, described, reported [1]. The lack research in this field stands the way a deeper understanding polypharmacology -and tremendous potential for therapy it bears. This Research Topic was edited by researchers working highlight important aspects on multiple levels, with focus membrane transporters prototypical protein group.A clear precise language fundamental concept polypharmacology. Stefan Rafehi thus provided first-in-field glossary describing relevant terminology within broader context drug discovery development [2]. interconnection used different areas supports interdisciplinary collaboration, which essential broad-scale assessments bioactivities characterize drugs. Thus, providing guideline use correct inclusive language, offer framework sustainable collaborative large-scale assessment platforms, sharing data, high-quality output.The conceptualization, development, validation new platforms identify validate novel targets requires repertoire tools. Here, Song, Zhang, Fu, coworkers described an easily applicable transferable LC-MS/MS-based workflow transporter function [3]. properties accurate description interpretation safety.The depends several factors, e.g., stereoselectivity toward chiral like verapamil, that bridge concepts stereoselectivity. Also, distribution chemical patterns [4][5][6][7] resultant physicochemistry [8] determine interactions various targets. On other hand, tendency certain accept ligands (i.e., polyspecificity) structural specificities, polymorphisms or (drug-selected) mutations, may be basis cross-resistance failure case efflux transporters. Gupta analyzed polyspecific frequently occurring mutations impact binding [9]. As turned out, polypharmacological substrates ('polysubstrates'), mitoxantrone, critically influenced key -suggesting existence 'backbone amino acids' constitute polyspecificity 'multitarget sites') [10,11].Concerning commonalities proteins are otherwise functionally phylogenetically distant from each other, 'translation between species' understand differences species project knowledge useful applications. Luckenbach Burkhardt-Medicke emphasized topic studying human zebrafish transporters, revealing operational temperature needs vary due homoio-and poikilotherm nature respective organisms [12]. However, although (related) work at conditions, polypharmacologicals such verapamil still exert findings contribute better polypharmacology.The regulation expression genetic changes. It could not only themselves, but also change pharmacology altered target modifier expression. Puris colleagues have focused female male mice applying polyanalytical approaches [13]. Sex inequality medical its relevance -is regularly neglected issue bears particular disease treatment equality public health services advanced therapies.In context, polypharmacy, has solid standing both classical pharmacotherapy traditional Chinese medicine. particularly true considering network multitarget ability variety structurally, functionally, and/or proteins, ion channels, kinases. Wang, Li, addressed aspect identifying bioactive constituents herbal formula, Qingdu Fang, bioinformatic [14].Amongst identified active ingredients quercetin, flavonoid known very rich -above all regarding -that indeed represents template addressing networks.Despite potential, disregarded independent (and important) field:(i) being actively denied purposes, claiming academic commercial focusing strategy improve therapeutic benefit. certainly untrue many (a) despite specificity [e.g., tyrosine kinase inhibitors (TKIs) central nervous system (CNS) drugs], (b) re-purposed tackle prevalent orphan diseases (e.g., acetylsalicylic acid, minoxidil, sildenafil, thalidomide, etc.), (c) intentionally developed engage tirzepatide), (d) combination therapy; collectively cancer, HIV infection, tuberculosis, etc.) [15];(ii) argued 'specificity key'. any ultimately prevent) improving safety discouraged, eventually resulting opposite: insufficiently characterized, less safe drugs;(iii) initially discovered deliberately designed bear affinities desired potentially undesired) either too similar leading off-target effects events. necessary optimize balance activities, support endorsement scientific communities;(iv) indeed, repurposing programs tedious, initial screenings against panel necessary. supporting programs, global whole strengthened, allowing local grow expertise rather than acquiring single (financially well-equipped) laboratory would undermine efforts green science, sustainability, research;(v) thorough provide druggability yet undruggable [16]. possibilities arrangement acids limited common motifs been earlier 'superfolds', 'supersites', [10,11], ('privileged ligands') specific entities showing activities distinct represent valuable tools [4][5][6][7][8]. since screening compounds most cases low potency, believe there no interest weak starting points further hit-to-lead optimization. Nevertheless, previous studies shown result potent promising hit molecules [17]. And even if activity favorable: one point always none;(vi) 'undruggability' newly often denied. claimed some surrogate target, issues assay resources effort communities -thereby questioning need privileged all. specifically these reasons can justify ligands: Undoubtedly, medicinal chemistry currently unable serve fields explore 'undruggable' Once properly identified, reported, inexpensive, accessible, enrich pool methodologies life sciences.In conclusion, matters -be designing There much more just 'dirty drugs', 'frequent hitters', 'bad actors' 'nuisance compounds' -it about risks. All contributors puzzle pieces our collective beneficial, safe,

Language: Английский

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