Stefan Katja, Puri Sachin, Rafehi Muhammad, Latambale Ganesh, Neif Maria, Tägl Franziska, Arlt Nike Sophia, Yazdi Zeinab Nezafat, Bakos Éva, Chen Xiang, Zhang Bohan, Ismail Al-Khalil Wouroud, Busch Hauke, Chen Zhe-Sheng, Özvegy-Laczka Csilla, Namasivayam Vigneshwaran, Juvale Kapil, Stefan Sven Marcel
University of Lübeck and University Medical Center Schleswig-Holstein, Lübeck Institute of Experimental Dermatology, Medicinal Chemistry and Systems Polypharmacology, Ratzeburger Allee 160, 23538, Lübeck, Germany; University of Oslo and Oslo University Hospital, Department of Pathology, Rikshospitalet, Sognsvannsveien 20, 0372, Oslo, Norway.
SVKM's NMIMS, Shobhaben Pratapbhai Patel School of Pharmacy & Technology Management, V.L. Mehta Road, Vile Parle (W), Mumbai, 400056, India; SVKM's NMIMS, School of Pharmacy & Technology Management, Plot no. B4, Green Industrial Park, Polepally SEZ, TSIIC, Jadcherla, Mahbubnagar, Dist. Telangana 509 301, Hyderabad, 509301, India.
Eur J Med Chem. 2025 Apr 5;287:117234. doi: 10.1016/j.ejmech.2024.117234. Epub 2025 Jan 2.
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.
