Medicinal Chemistry Education: Emphasize Fundamentals and Skillfully Integrate Knowledge

Abstract

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.