吲哚基特权配体的功能和结构多药理学以解决膜转运体的不可药物性

IF 6 2区 医学 Q1 CHEMISTRY, MEDICINAL European Journal of Medicinal Chemistry Pub Date : 2025-01-02 DOI:10.1016/j.ejmech.2024.117234
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
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引用次数: 0

摘要

尽管溶质载体(SLC)和atp结合盒(ABC)转运体在人类健康和疾病中发挥着重要作用,但大多数仍未被描述为未知的内在和/或外源配体,使其成为“不可药物”。多药理学被定义为一个配体同时作用多个靶点,为发现新的先导化合物提供了一条有希望的途径,以解决这些新兴的药理学挑战-当代药物化学的主要焦点。虽然通过“多靶点结合位点”的概念,已经提出了系统发育多样性蛋白质之间的共同结构基序,作为多药理学的基础,但尚未从药物化学的角度对这些功能和结构方面进行全面分析。在我们的研究中,我们合成了65种不同的茚唑衍生物,并在包含17种特异性和多特异性SLC和ABC转运蛋白的广泛生物学评估平台上评估了它们的活性。值得注意的是,10种茚唑类化合物对与神经变性(ABCA1)、代谢重编程(MCT4)和癌症多药耐药(ABCC10)相关的转运蛋白靶点具有交叉靶标活性。一种铅分子对这些评估的靶标表现出特殊的效力。此外,分子盲对接实验和高级结合位点分析首次揭示了mct、有机阴离子转运多肽(OATPs)、有机阳离子转运蛋白(OCTs)和ABC转运蛋白之间的保守结合基序,其特征是酪氨酸、苯丙氨酸、丝氨酸和苏氨酸的特异性和重复残基。这些发现不仅突出了多药理学在药物发现中的潜力,而且还提供了对跨膜转运体配体结合的结构基础的见解。
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Functional and Structural Polypharmacology of Indazole-based Privileged Ligands to Tackle the Undruggability of Membrane Transporters
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 indazole compounds exhibited cross-target activity against challenging transporter targets associated with neurodegeneration (ABCA1), metabolic reprogramming (MCT4), and cancer multidrug resistance (ABCC10). One lead molecule demonstrated exceptional potency against these assessed targets. Furthermore, molecular blind docking experiments and advanced binding site analyses revealed, for the first time, conserved binding motifs across 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.
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来源期刊
CiteScore
11.70
自引率
9.00%
发文量
863
审稿时长
29 days
期刊介绍: The European Journal of Medicinal Chemistry is a global journal that publishes studies on all aspects of medicinal chemistry. It provides a medium for publication of original papers and also welcomes critical review papers. A typical paper would report on the organic synthesis, characterization and pharmacological evaluation of compounds. Other topics of interest are drug design, QSAR, molecular modeling, drug-receptor interactions, molecular aspects of drug metabolism, prodrug synthesis and drug targeting. The journal expects manuscripts to present the rational for a study, provide insight into the design of compounds or understanding of mechanism, or clarify the targets.
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