Introduction: G protein-coupled receptors (GPCRs) are a large, well-known group of membrane receptors that are among the most important therapeutic targets. Activation of GPCRs by extracellular stimuli initiates signal transduction that ultimately leads to the response. The crystal structure of GPCRs by crystallization protocol is difficult to obtain, because it is difficult to remove and purify them from membranes. One of the GPCRs whose crystal structure has been determined is P2Y12 (PDB: 4PXZ). P2Y12 is one of the major GPCRs whose job is to stabilize platelet aggregation in blood tissue formation, making this receptor a critical target for current antiplatelet therapy [1]. In my proposed research, I targeted G protein-coupled receptor 171 (GPR171), which was recently discovered as a receptor for modulating appetite and metabolism in mice. The biological role of GPCR171 and the gene that encodes it (GPR171) has received much attention recently, and is found to involve diet and metabolism in mice [2] and myeloid differentiation [3]. GPR171 was also found to be overexpressed in lung cancer tissues, suggesting that it is a promising target for antineoplastic drug development. [4]Say no to plagiarism. Get a tailor-made essay on “Why violent video games should not be banned”?Get the original essaySince GPR171 is expressed in the part of the brain responsible for psychological disorders, it was recently discovered that it may be used as a new target for developing anxiolytics.[5] Until recently, GPCR171 was considered an orphan receptor, as its natural agonist, BigLen, was discovered not long ago. BigLen is a 16 amino acid neuropeptide (LENSSPQAPARRLLPP) that acts as a natural GPCR171 agonist in the hypothalamus. Its binding affinity for GPCR171 is high (low Kd = 0.5 Nm). The structural requirement for BigLen that is essential for binding to its target was discovered by the drug design approach called drug simplification, that is, cutting the endopeptide piece by piece. Finally, after numerous tests, it was found that only four amino acids (LLPP) from the C-terminus are enough to trigger the receptor [2]. These discoveries initiated the development of small chemical ligands capable of selectively activating or deactivating GPR171. Since there is no crystal structure of GPR171, homology modeling is an alternative option. For cooperation, the P2Y receptor 12 was used, because they are phylogenetically related, as shown by comparison of their homologous sequences. The mechanism of action of the P2Y12 receptor demonstrates that the binding of ADP in the extracellular domain of the receptor initiates the cascade of events inside the cell. Examination of the crystal structure of P2Y12 revealed that the binding pocket of this receptor has a histidine side chain essential for receptor activity. This was proven by the fact that when histidine is replaced by glutamine, the activity of the receptor is disrupted.[1] In ligand binding assays, it was found that ligands like 2MeSADP, ADP, and ADPβS that bind to the P2Y12 receptor are not active toward GPCR171 as they do not displace its natural ligand BigLen. These observations suggest that there is a significant structural difference in the binding site of GPR171 and P2Y12. However, the atomic coordinates of the 4PXZ PDB file are all that are available to thread the GPR171 amino acid sequence. Fig. 1. [2].