Medicinal chemistry is an interdisciplinary field that aims to discover innovative drugs and synthesize drug molecules at the intersection of chemistry and biology. In the field of medicinal chemistry education, it is essential to establish a robust foundation by emphasizing fundamental principles of chemistry and biology. This strategy not only imparts students with a comprehensive understanding of core concepts but also equips them with the requisite skills to effectively apply this knowledge in their future pursuits. Bioisosteric replacement is a commonly used and effective drug design strategy that involves reactions such as acylation and alkylation. However, this leads to students only mastering these reactions and shying away from more complex ones. As a fundamental component of medicinal chemistry education, a robust foundation in chemistry is imperative. With advancements in organic chemistry, numerous reactions─such as click chemistry, multicomponent reactions, molecular editing (1−5)─and tools─including photocatalysis, biocatalysis, and asymmetric catalysis (6−9)─have emerged. These developments have greatly facilitated progress in medicinal chemistry. By employing click chemistry, we can efficiently synthesize a diverse array of valuable molecules, which is particularly advantageous in the realms of drug design and discovery. Our research group has utilized this approach to identify compounds exhibiting high activity against the main protease of SARS-CoV-2 and its variants. (4) The multicomponent reactions enable the efficient synthesis of a diverse array of compounds throughout the drug discovery process, thereby expediting the screening of potential drug candidates. (10) In the synthesis of isocyanide compounds exhibiting activity against the main protease of SARS-CoV, the Ugi reaction plays a pivotal role. (2) The application of molecular editing techniques enables the rapid synthesis of a diverse array of compounds, thereby expediting the screening process for potential drug candidates. The substitution of a single carbon atom in the pyridine ring with a nitrogen atom led to the development of avanafil, an FDA-approved medication that demonstrated a 20-fold increase in potency. (11) Additionally, photocatalysis, biocatalysis, and asymmetric catalysis represent potent methodologies for the synthesis of intricate pharmaceutical compounds. (6−9) In addition to a robust foundation in chemistry, proficiency in drug design is essential for students pursuing medicinal chemistry. Computer-aided drug design (CADD) serves as a pivotal tool within the realm of drug development. This approach utilizes various technologies, including computer technology, computational chemistry, computational biology, molecular graphics, mathematical statistics, and databases, to explore the interactions between drugs and their respective receptors. The objective is to establish a methodological framework for discovering, designing, and optimizing innovative drug molecules. The advancement of CADD is critically important for enhancing the efficiency of drug development processes by shortening research timelines and reducing associated costs. (12,13) Particularly during the early stages of novel disease outbreaks, this method can swiftly identify candidate drugs. For instance, during the initial phase of the COVID-19 outbreak, virtual screening successfully identified a lead compound with an EC₅₀ value of 77 nM. (14) Furthermore, we must wholeheartedly embrace the advancements in artificial intelligence (AI), which has the potential to significantly expedite the drug development pipeline. AI can drastically reduce the time consumed in crucial stages such as drug target identification, molecular design, and optimization. A prime example of this efficiency is the discovery of the candidate molecule INS018_055, which required the synthesis and testing of less than 80 molecules. Remarkably, only 18 months post-target discovery, INS018_055 was designated as a preclinical candidate. This rapid progression culminated in the announcement of its phase 2 clinical trials in June 2023, underscoring the transformative impact of AI in expediting drug development and bringing us closer to life-saving therapies. (15) Biology is the cornerstone of the life sciences, providing a comprehensive understanding of life’s complexities and enabling advancements in medicine, agriculture, environmental management, and other fields that depend on deep insights into living systems. The advancements in biochemical principles have promoted the development of new drug design methodologies. As research advances, a diverse array of methods for modulating the spatial distances between molecules has been utilized in drug design. The foundational principle underlying this concept is the phenomenon known as chemically induced proximity (CIP). (16) It is a technique that regulates intermolecular distances by utilizing small molecules capable of permeating cell membranes. This technology has broad applications in the fields of biology and medicine. CIP technology can be employed to modulate various biological processes, including signal transduction, transcription, protein degradation, epigenetic memory, and chromatin dynamics. A key application of CIP technology is protein degradation, in which molecular glues and proteolysis-targeting chimeras (PROTACs) represent two primary strategies. These approaches not only facilitate the degradation of intracellular proteins but also extend to extracellular proteins, transmembrane proteins, intracellular protein aggregates, and even organelles. This significantly broadens the scope of degradable proteomes and enhances the therapeutic potential for targeted protein degradation. (17) According to an online database of PROTACs, the most extensively studied targets include estrogen receptor, androgen receptor, BTK, ALK, BCR-ABL, and BRD4. (18) In addition to facilitating protein degradation, CIP technology can also be employed to induce post-translational modifications of proteins and to develop advanced cellular therapy modalities. For example, it allows for the temporary control of chimeric antigen receptor (CAR)-T cell therapies through chemically induced proximity. The CAR in CAR-T therapy plays a crucial role in enhancing immune responses as well as promoting the downstream activation and proliferation of T cells. However, excessive activation of T cells may result in toxicities associated with cell therapies. As a consequence, various CAR-T technologies have been developed; these include engineering CAR-T cells using rimiducid as an ON/OFF switch, along with employing lenalidomide for similar purposes. (19,20) These modifications are designed to modify the structure of chimeric antigen receptors, thereby enhancing control over immune responses and T cell activation. Ultimately, this approach aims to provide a more manageable and safer treatment option for patients. To enhance the learning experience, educators should adeptly integrate various facets of medicinal chemistry. This integration can manifest in multiple forms, such as combining theoretical knowledge with practical laboratory work or merging the study of chemical structures with an understanding of their biological activities. By adopting this approach, students can attain a comprehensive perspective on the subject and recognize the interconnectedness among different areas within the field. Moreover, incorporating modern technologies and interdisciplinary methodologies can further enrich the educational experience. By combining radionuclide therapies, covalent strategies, and click chemistry, SuFEx-engineered fibroblast activation protein inhibitors (FAPIs) have demonstrated enhanced tumor uptake compared to the original FAPI and improved tumor retention by a factor of 13. (21) Through structure-based drug design and modular synthesis, a substantial number of target compounds can be rapidly obtained. This set of methods was employed for the modification of antibacterial compounds, resulting in the development of antibiotic candidates that are effective against resistant strains. (22) Thanks to advancements in AI, the automation of the molecular design–make–test–analyze cycle significantly accelerates the identification of hits and leads in drug discovery. Using deep learning techniques for molecular design, coupled with a microfluidics platform for on-chip chemical synthesis, liver X receptor (LXR) agonists were generated de novo. Twenty-five de novo designs were successfully synthesized using a flow approach. In vitro screening of the crude reaction products identified 17 hits (68%), demonstrating up to 60-fold activation of LXR. Subsequent batch resynthesis, purification, and retesting of 14 of these compounds confirmed that 12 exhibited potent LXR agonist activity. (23) In summary, a comprehensive education in medicinal chemistry should prioritize foundational knowledge while simultaneously promoting the adept integration of this knowledge. This balanced approach not only fosters a deeper understanding but also equips students to navigate the complexities of the pharmaceutical industry. Furthermore, by incorporating systems biology education, innovating teaching methodologies, establishing collaborative models between industry and academia, and developing cutting-edge case studies in drug development, medicinal chemistry education can more effectively address global health challenges. This strategy aims to cultivate talents capable of advancing drug research and innovation. We gratefully acknowledge financial support from Shandong Undergraduate Teaching Reform Research Project (M2023290), Qilu Medical College Undergraduate Education Teaching Research Project (qlyxjy-202309), the National Natural Science Foundation of China (22208191, 22273049), Major Basic Research Project of Shandong Provincial Natural Science Foundation (ZR2021ZD17), Guangdong Basic and Applied Basic Research Foundation (2021A1515110740), and Shandong Laboratory Program (SYS202205). This article references 23 other publications. This article has not yet been cited by other publications.

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药物化学教育：强调基础，巧妙整合知识


药物化学是一个跨学科领域，旨在发现创新药物并在化学和生物学的交叉点合成药物分子。在药物化学教育领域，必须通过强调化学和生物学的基本原理来建立坚实的基础。这种策略不仅使学生对核心概念有全面的理解，而且还使他们具备必要的技能，以便将这些知识有效地应用于未来的追求。生物等排置换是一种常用且有效的药物设计策略，涉及酰化和烷基化等反应。然而，这导致学生只掌握这些反应而回避更复杂的反应。作为药物化学教育的基本组成部分，坚实的化学基础势在必行。随着有机化学的进步，出现了许多反应，如点击化学、多组分反应、分子编辑 （1-5）和工具，包括光催化、生物催化和不对称催化 （6-9）。这些发展极大地促进了药物化学的进步。通过采用点击化学，我们可以有效地合成各种有价值的分子，这在药物设计和发现领域特别有利。我们的研究小组利用这种方法来识别对 SARS-CoV-2 及其变体的主要蛋白酶表现出高活性的化合物。（4） 多组分反应能够在整个药物发现过程中高效合成多种化合物，从而加快潜在候选药物的筛选。 （10） 在对 SARS-CoV 主要蛋白酶具有活性的异氰化物化合物的合成中，Ugi 反应起着关键作用。（2） 分子编辑技术的应用能够快速合成多种化合物，从而加快潜在候选药物的筛选过程。吡啶环中的单个碳原子被氮原子取代，导致了阿伐那非的开发，阿伐那非是一种 FDA 批准的药物，其效力提高了 20 倍。（11） 此外，光催化、生物催化和不对称催化是合成复杂药物化合物的有效方法。（6-9） 除了坚实的化学基础外，熟练的药物设计对于追求药物化学的学生来说也是必不可少的。计算机辅助药物设计 （CADD） 是药物开发领域的关键工具。这种方法利用各种技术，包括计算机技术、计算化学、计算生物学、分子图形学、数理统计和数据库，来探索药物与其各自受体之间的相互作用。目标是建立发现、设计和优化创新药物分子的方法框架。CADD 的进步对于通过缩短研究时间和降低相关成本来提高药物开发过程的效率至关重要。（12,13） 特别是在新型疾病爆发的早期阶段，这种方法可以迅速识别候选药物。例如，在 COVID-19 爆发的初始阶段，虚拟筛选成功鉴定了 EC₅₀ 值为 77 nM 的先导化合物。 （14） 此外，我们必须全心全意地拥抱人工智能 （AI） 的进步，这有可能显着加快药物开发管道。AI 可以大大减少药物靶点识别、分子设计和优化等关键阶段所消耗的时间。这种效率的一个主要例子是发现候选分子INS018_055，这需要合成和测试不到 80 个分子。值得注意的是，在靶点发现后仅 18 个月，INS018_055 就被指定为临床前候选药物。这种快速进展最终于 2023 年 6 月宣布了其 2 期临床试验，突显了人工智能在加速药物开发和使我们更接近拯救生命的疗法方面的变革性影响。（15） 生物学是生命科学的基石，它提供了对生命复杂性的全面理解，并推动了医学、农业、环境管理和其他依赖于对生命系统的深刻见解的领域的进步。生化原理的进步促进了新药设计方法的发展。随着研究的进步，药物设计中采用了多种方法来调节分子之间的空间距离。这个概念的基本原理是被称为化学诱导接近 （CIP） 的现象。（16） 这是一种通过利用能够渗透细胞膜的小分子来调节分子间距离的技术。这项技术在生物学和医学领域具有广泛的应用。 CIP 技术可用于调节各种生物过程，包括信号转导、转录、蛋白质降解、表观遗传记忆和染色质动力学。CIP 技术的一个关键应用是蛋白质降解，其中分子胶和蛋白水解靶向嵌合体 （PROTAC） 代表了两种主要策略。这些方法不仅促进细胞内蛋白质的降解，而且还延伸到细胞外蛋白质、跨膜蛋白、细胞内蛋白质聚集体，甚至细胞器。这显著拓宽了可降解蛋白质组的范围，并增强了靶向蛋白质降解的治疗潜力。（17） 根据 PROTACs 的在线数据库，研究最广泛的靶点包括雌激素受体、雄激素受体、BTK、ALK、BCR-ABL 和 BRD4。（18） 除了促进蛋白质降解外，CIP 技术还可用于诱导蛋白质的翻译后修饰并开发先进的细胞治疗方式。例如，它允许通过化学诱导的接近来临时控制嵌合抗原受体 （CAR）-T 细胞疗法。CAR-T 疗法中的 CAR 在增强免疫反应以及促进 T 细胞的下游活化和增殖方面起着至关重要的作用。然而，T 细胞的过度激活可能会导致与细胞疗法相关的毒性。因此，已经开发了各种 CAR-T 技术;其中包括使用 rimiducid 作为 ON/OFF 开关来改造 CAR-T 细胞，以及用于类似目的的来那度胺。（19,20） 这些修饰旨在改变嵌合抗原受体的结构，从而增强对免疫反应和 T 细胞活化的控制。 最终，这种方法旨在为患者提供更易管理、更安全的治疗选择。为了增强学习体验，教育工作者应该熟练地整合药物化学的各个方面。这种整合可以以多种形式表现出来，例如将理论知识与实际实验室工作相结合，或者将化学结构的研究与其生物活动的理解相结合。通过采用这种方法，学生可以获得对该主题的全面认识，并认识到该领域内不同领域之间的相互联系。此外，结合现代技术和跨学科方法可以进一步丰富教育体验。通过结合放射性核素疗法、共价策略和点击化学，SuFEx 工程成纤维细胞活化蛋白抑制剂 （FAPI） 与原始 FAPI 相比，肿瘤摄取增强，肿瘤保留率提高了 13 倍。（21） 通过基于结构的药物设计和模块化合成，可以快速获得大量的目标化合物。这套方法用于抗菌化合物的修饰，从而开发出对耐药菌株有效的候选抗生素。（22） 得益于人工智能的进步，分子设计-制造-测试-分析周期的自动化显著加快了药物发现中靶点和先导化合物的识别。使用深度学习技术进行分子设计，再加上用于芯片化学合成的微流体平台，从头生成肝脏 X 受体 （LXR） 激动剂。使用流动方法成功合成了 25 种从头设计。 粗反应产物的体外筛选确定了 17 个 命中 （68%），表明 LXR 的激活率高达 60 倍。随后对其中 14 种化合物的批量再合成、纯化和重新测试证实，12 种表现出有效的 LXR 激动剂活性。（23） 总之，药物化学的全面教育应优先考虑基础知识，同时促进这些知识的熟练整合。这种平衡的方法不仅促进了更深入的理解，而且使学生能够驾驭制药行业的复杂性。此外，通过整合系统生物学教育、创新教学方法、建立工业界和学术界之间的合作模式以及开发药物开发的前沿案例研究，药物化学教育可以更有效地应对全球健康挑战。该战略旨在培养能够推动药物研究和创新能力的人才。感谢山东省本科教学改革研究项目（M2023290）、齐鲁医学院本科教育教学研究项目（qlyxjy-202309）、国家自然科学基金（22208191、22273049、山东省自然科学基金重大基础研究项目（ZR2021ZD17）、广东省基础与应用基础研究基金（2021A1515110740）和山东省实验室计划（SYS202205）的财政支持。本文引用了其他 23 种出版物。本文尚未被其他出版物引用。