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G-protein-coupled receptors (GPCRs) represent the most extensive and varied group of membrane receptors, playing a crucial role in mediating cellular signaling and maintaining physiological functions. These receptors play essential roles in controlling inflammation, immune responses, neurotransmission, and metabolic balance. Due to their extensive involvement in signaling pathways, GPCRs have become the most successful targets in modern pharmacotherapy, influencing nearly 34% of all approved drugs. This chapter provides an in-depth analysis of GPCR structure, function, and pharmacological significance, emphasizing their involvement in various pathological conditions, such as neurodegenerative, cardiovascular, endocrine, and inflammatory diseases. The chapter highlights the mechanisms of GPCR signaling, including G-protein-dependent and β-arrestin-mediated pathways, and discusses their therapeutic relevance in disease modulation. It further examines recent progress in GPCR-focused drug discovery, encompassing high-throughput screening (HTS), structure-based drug design (SBDD), and computational modelling techniques. The emergence of cryo-electron microscopy (cryo-EM) and artificial intelligence (AI)-assisted protein modelling has transformed our structural insights into GPCRs, facilitating the rapid development of selective agonists, antagonists, and allosteric modulators. Furthermore, the chapter discusses emerging concepts such as biased signaling, deorphanization of GPCRs, and the potential of GPCR-targeted degradation technologies like PROTACs. Despite tremendous progress, challenges such as receptor desensitization, subtype selectivity, and off-target effects continue to hinder clinical translation. Nevertheless, GPCR research continues to evolve toward precision medicine, offering novel insights into receptor dynamics and ligand-receptor interactions. Overall, this chapter consolidates current knowledge of GPCR biology and drug discovery, underscoring their immense therapeutic potential and inspiring future innovations aimed at developing safer and more effective GPCR-based therapies for diverse human diseases.

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Strategies for GPCR-Directed Disease Management

  • 章节

  • 发表日期：

    2026年

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  • M. R. Pradeep Kumar,
  • B. S. Manya

摘要

G-protein-coupled receptors (GPCRs) represent the most extensive and varied group of membrane receptors, playing a crucial role in mediating cellular signaling and maintaining physiological functions. These receptors play essential roles in controlling inflammation, immune responses, neurotransmission, and metabolic balance. Due to their extensive involvement in signaling pathways, GPCRs have become the most successful targets in modern pharmacotherapy, influencing nearly 34% of all approved drugs. This chapter provides an in-depth analysis of GPCR structure, function, and pharmacological significance, emphasizing their involvement in various pathological conditions, such as neurodegenerative, cardiovascular, endocrine, and inflammatory diseases. The chapter highlights the mechanisms of GPCR signaling, including G-protein-dependent and β-arrestin-mediated pathways, and discusses their therapeutic relevance in disease modulation. It further examines recent progress in GPCR-focused drug discovery, encompassing high-throughput screening (HTS), structure-based drug design (SBDD), and computational modelling techniques. The emergence of cryo-electron microscopy (cryo-EM) and artificial intelligence (AI)-assisted protein modelling has transformed our structural insights into GPCRs, facilitating the rapid development of selective agonists, antagonists, and allosteric modulators. Furthermore, the chapter discusses emerging concepts such as biased signaling, deorphanization of GPCRs, and the potential of GPCR-targeted degradation technologies like PROTACs. Despite tremendous progress, challenges such as receptor desensitization, subtype selectivity, and off-target effects continue to hinder clinical translation. Nevertheless, GPCR research continues to evolve toward precision medicine, offering novel insights into receptor dynamics and ligand-receptor interactions. Overall, this chapter consolidates current knowledge of GPCR biology and drug discovery, underscoring their immense therapeutic potential and inspiring future innovations aimed at developing safer and more effective GPCR-based therapies for diverse human diseases.