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4 A P P L I C A T I O N N O T E Membrane protein – Small molecule interaction: P2X4 and 5-BDBD The P2X purinoceptor 4 (P2X4), a member of the P2X family of ligand-gated ion channels, plays a crucial role in mediating the cellular response to extracellular adenosine triphosphate (ATP) (1). Biologically, P2X4 receptors have a trimeric structure and are permeable to cations such as calcium (Ca²⁺), sodium (Na⁺), and potassi- um (K⁺), which can initiate various intracellular signaling cascades (2,3). The receptor is widely expressed in immune cells, such as microglia, neurons, and endothelial cells, where it influ- ences processes like neurotransmission, inflam- mation, and immune response (4). One key aspect of its function is in the central nervous system, where P2X4 is implicated in synaptic plasticity and neuropathic pain pathways (5), by promoting the release of pro-inflammatory cytokines and other mediators from microglia. From a therapeutic perspective, the P2X4 recep- tor has garnered considerable interest as a drug target due to its involvement in pathological conditions, particularly neuropathic pain and inflammation (5). Its role in microglia activation, especially in the spinal cord during chronic pain states, has highlighted its relevance in develop- ing novel pain therapeutics (6). Given its role in mediating neuropathic pain and inflammation, the discovery of P2X4 antagonists could lead to new therapies for chronic pain conditions that are resistant to current treatments. These mol- ecules could selectively block the receptor's ac- tivity in microglia, thereby reducing the release of pro-inflammatory cytokines and attenuating pain signaling pathways. Membrane protein – Peptide interaction: GLP1R and Exendin 9-39 The Glucagon-Like Peptide-1 Receptor (GLP1R) plays a crucial role in managing blood sugar and maintaining energy balance. It is part of the G-protein-coupled receptor (GPCR) family, which helps transmit signals across cell mem- branes. GLP1R is mainly found in pancreatic β-cells, where its activation triggers insulin re- lease when blood sugar levels rise. It also lowers glucagon secretion, a hormone that increases blood sugar, and slows down stomach empty- ing, helping to control post-meal glucose levels (7). Beyond regulating glucose, GLP1R is also present in the brain, where it affects appetite, and in the cardiovascular system, offering po- tential heart benefits (8).