Functional and structural polypharmacology of indazole-based privileged ligands to tackle the undruggability of membrane transporters
Year: 2025
Type: article
Abstract: Despite the significant roles of solute carrier (SLC) and ATP-binding cassette (ABC) transporters in human health and disease, most remain poorly characterized as intrinsic and/or xenobiotic ligands are unknown, rendering them as 'undruggable'. Polypharmacology, defined as the simultaneous engagement of multiple targets by a single ligand, offers a promising avenue for discovering novel lead compounds addressing these emerging pharmacological challenges - a major focus in contemporary medicinal chemistry. While common structural motifs among phylogenetically diverse proteins have been proposed to underlie polypharmacology through the concept of 'multitarget binding sites', a comprehensive analysis of these functional and structural aspects from a medicinal chemistry perspective has yet to be undertaken. In our study, we synthesized 65 distinct indazole derivatives and evaluated their activity across a broad biological assessment platform encompassing 17 specific and polyspecific SLC and ABC transporters. Notably, ten indazoles exhibited cross-target activity against challenging transporter targets associated with neurodegeneration (ABCA1), metabolic reprogramming (MCT4), and cancer multidrug resistance (ABCC10). Furthermore, molecular blind docking experiments and advanced binding site analyses revealed, for the first time, conserved binding motifs across monocarboxylate transporters (MCTs), organic anion transporting polypeptides (OATPs), organic cation transporters (OCTs), and ABC transporters, characterized by specific and recurring residues of tyrosine, phenylalanine, serine, and threonine. These findings highlight not only the potential of polypharmacology in drug discovery but also provide insights into the structural underpinnings of ligand binding across membrane transporters.
Authors: Katja Stefan, Sachin Puri, Muhammad Rafehi, Ganesh Latambale, Maria Neif, Franziska Tägl, Nike Sophia Arlt, Zeinab Nezafat Yazdi, Éva Bakos, Xiang Chen, Bohan Zhang, Wouroud Ismail Al-Khalil, Hauke Busch, Zhe-Sheng Chen, Csilla Özvegy-Laczka, Vigneshwaran Namasivayam, Kapil Juvale, Sven Marcel Stefan
Institutions: Oslo University Hospital, University of Oslo, University of Lübeck, Narsee Monjee Institute of Management Studies, Shri Vile Parle Kelavani Mandal, University of Augsburg, University Hospital Augsburg, Universitätsmedizin Göttingen, University of Göttingen, HUN-REN Research Centre for Natural Sciences, St. John's University, University of Bonn, Medical University of Lublin
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $4,650
Funders: Collaborative Research in Engineering, Science and Technology Centre, Deutscher Akademischer Austauschdienst, Deutsche Forschungsgemeinschaft, Georg-August-Universität Göttingen, Hungarian Scientific Research Fund, Rheinische Friedrich-Wilhelms-Universität Bonn, Julius-Maximilians-Universität Würzburg, Nemzeti Kutatási Fejlesztési és Innovációs Hivatal, Science and Engineering Research Board
Awards: Rückkehrstipendium, Etablierung neuer Detektionsmethoden zur Entdeckung und Entwicklung neuer ABCA1 und ABCA7 Modulatoren als Alzheimer Therapeutika und Diagnostika, Untersuchungen zur Stereoselektivität von genetisch variablen Arzneistoffmembrantransportern der Solute Carrier Familie für ein besseres molekulares Verständnis und die Entwicklung sicherer Arzneimitteltherapien, Design, Synthese und biologische Bewertung von ABC TransporterAgonisten zur Entwicklung neuer Alzheimer Therapeutika, G2774449326, G3129451782, EXC 2167: Präzisionsmedizin für Chronische Entzündungserkrankungen (PMI), G3934316266, G7150644171, Exploration von PanABCTransporterModulatoren durch innovative In Silico und In Vitro Methoden zur Generierung potentieller Zielstrukturen, Diagnostika und Therapeutika, G7705503227, G83165825
OpenAlex ID: W4405982535