Medicinal Chemistry Education: Molecular Level Understanding of All Medicinal Properties and Innovative Strategies

InfoMetricsFiguresRef. Journal of Medicinal ChemistryASAPArticle This publication is free to access through this site. Learn More CiteCitationCitation and abstractCitation and referencesMore citation options ShareShare onFacebookX (Twitter)WeChatLinkedInRedditEmailJump toExpandCollapse EditorialOctober 24, 2024Medicinal Chemistry Education: Molecular Level Understanding of All Medicinal Properties and Innovative StrategiesClick to copy article linkArticle link copied!Sankar K. Guchhait*Sankar K. GuchhaitDepartment of Medicinal Chemistry National Institute of Pharmaceutical Education and Research (NIPER), S. A. S. Nagar (Mohali), Punjab 160062, India*[email protected]; skguchhait.comMore by Sankar K. Guchhaithttps://orcid.org/0000-0002-1817-2172Open PDFJournal of Medicinal ChemistryCite this: J. Med. Chem. 2024, XXXX, XXX, XXX-XXXClick to copy citationCitation copied!https://pubs.acs.org/doi/10.1021/acs.jmedchem.4c02460https://doi.org/10.1021/acs.jmedchem.4c02460Published October 24, 2024 Publication History Received 11 October 2024Published online 24 October 2024editorialPublished 2024 by American Chemical Society. This publication is available under these Terms of Use. Request reuse permissionsThis publication is licensed for personal use by The American Chemical Society. ACS PublicationsPublished 2024 by American Chemical Society Medicinal Chemistry Education – A Unique ModelStudents who join graduate (Master's degree) education programs in medicinal chemistry include primarily those having a pharmacy/pharmaceutical science background in their undergraduate studies (Bachelor's degree) but also students from purely biology or chemistry areas, especially synthetic organic chemistry. Creating a system to educate students of such diverse backgrounds in medicinal chemistry─an interdisciplinary professional science domain that by its nature comprises various branches of chemistry, especially organic, physical, and computational chemistry but also pharmacognosy, biology, and pharmacology─is interesting but challenging. Research and outcomes in medicinal chemistry have been progressing tremendous well, and the drug discovery and development field is rapidly evolving. The subject is essential to health science and directly linked with research and work done by pharmaceutical companies. Therefore, medicinal chemistry education requires course contents to be continuously linked with research advancements in the pharmaceutical industry and to encompass the unique strategies of theory, practice, projects, internships, and seminar-based education in the subject, which are valuable to develop students' knowledge, creative thinking ability in research, and team-working skills. Cultivating quality human resources with appropriate knowledge and skills in medicinal chemistry is critical to meet the pharmaceutical industry's needs for quality professionals for R&D production with efficiency and effectiveness. These human resources will also be responsible for the future progress in academic research in medicinal chemistry. Thus, today's educators (teachers, course designers, and policy makers) are required to play a significant role in developing an effective educational system in the discipline. How Medicinal Chemistry Is Taught in Pharmaceutical Science Schools: Past and PresentIn past decades, medicinal chemistry undergraduate and graduate education mostly focused on drugs' clinical uses with classifications, modes of action, syntheses of a few drugs having simple molecular structures, common organic reactions, functional group transformations, natural products, sources, biological properties, traditional therapeutic uses, isolation methods, pharmacology, toxicology, formulations, various analytical and spectroscopic instruments, intellectual property rights, pharmacopoeia, and drug regulatory aspects. Students, educators, researchers, and the global scenario used to consider the subject of medicinal chemistry as a multidisciplinary mixture of chemistry, biology, and pharmacology. In the past few years, medicinal chemistry research has progressed exceedingly well and contributes highly to health science. Currently, medicinal chemistry education emphasizes 1) a molecular level understanding of what an exogeneous molecule can do in the human body as well as what the body can do to the exogeneous molecule, 2) a molecular level understanding of all medicinal properties, and 3) innovative strategies for drug discovery and development. Medicinal properties are explained in terms of molecular, electronic, and chemical behavior linked with in vitro and in vivo pharmacodynamics, physicochemical behavior, a profile of adsorption, distribution, metabolism, excretion, and toxicity (ADMET) properties, and pharmacokinetics. Among the physicochemical properties, a variety of parameters are taught, such as hydrogen bond donor and acceptor sites, rotatable bonds, percentage of sp3 centers, solubility, lipophilicity, cell membrane permeability, and various filters (e.g., Lipinski, Brenk, PAINS). Innovative strategies in medicinal chemistry include induced proximity approaches, such as proteolysis targeting chimeras (PROTACs), molecular glues, and TAC-based methods; antibody–drug conjugates (ADCs); natural-product-inspired approaches; scaffold hopping; drug repurposing; AI/ML-based prediction; structure, ligand, fragment, or de novo-based design; proteomics and genomics; and photodynamic approaches. Both undergraduate and graduate students learn about the drug and natural product privileged motifs, heterocyclic or molecular skeletons frequently present in drugs, and various statistics. Nowadays, the syntheses of all U.S. FDA-approved drugs are published, and the organic reactions that are frequently used in the syntheses of drugs are well explored. Some of these drugs' syntheses and the organic reactions are taught to students. In academia, medicinal chemistry is regarded as a distinct scientific subject. In actuality, medicinal chemistry is a central science area comprising knowledge of all branches of pharmaceutical sciences, including pharmacoinformatics, bioinformatics, chemoinformatics, chemistry and syntheses (mostly organic syntheses), natural products, biology, pharmacology, toxicology, pharmaceutics preformulation, drug delivery, and medical science. In past decades, undergraduate education in pharmacy schools focused, in general, on sharing information on pharmacy with only one question: "what?" But students did not learn the answers to questions on the molecular basis of pharmaceutical sciences: "why and how?" Therefore, in recent times, with enormous growth of research, outcomes, and perspectives, the undergraduate and graduate education in medicinal chemistry focuses on explaining the molecular basis of all medicinal properties, case studies of molecules developed as pharmaceuticals (new drugs from concept to market), greener drugs (environmental concerns), strategies, molecular design rationale and structural modulations, computer-aided studies, greener synthesis, molecular diversity-feasible access to compounds, biophysical and in vivo experiments to evaluate molecular properties, and how all these aspects are considered collectively in investigations to improve pharmacodynamics, physicochemistry, ADMET, and pharmacokinetic profiles.Study the past if you would define the future. – ConfuciusThis philosophy is also true in drug discovery and development. U.S. FDA-approved drug molecules are being frequently analyzed to frame new ways of thinking and strategies for novel therapeutic discovery and development. Our current education in medicinal chemistry includes remarkable recent analyses on various aspects, results, and reasons, such as physicochemical properties of drugs relevant to oral bioavailability, ADMET and pharmacokinetics, high-frequency presence of drug-important structural motifs (heterocyclic, aromatic, or heteroaromatic rings, functional groups, and functionalized side chains or appended motifs), natural products as sources of new drugs, and synthetic approaches to new drugs. "The most fruitful basis for the discovery of a new drug is to start with an old drug," said Sir James W. Black, winner of the 1988 Nobel Prize in Physiology or Medicine. Sir James's wisdom clearly indicates that a molecular level understanding of a drug's function should be at the origin of rational drug design. All these resources for molecular analysis and knowledge about drugs and natural products are therefore currently imparted to students in medicinal chemistry education. How Classical Synthetic Organic Chemists Learn Medicinal Chemistry "On the Job" in Academia and IndustryA synthetic organic chemist by training is fundamentally knowledgeable, skilled, and a creative thinker about organic molecular structure and the electronic and molecular behavior of such molecules, physicochemical interactions between one molecule and another molecule, chemical reactions (bond-breaking and -making) of different functional groups and motifs, development of reaction methods and synthetic approaches, green chemistry principles, the molecular responses and interactions that a molecule shows to biomacromolecules, and the use of a wide range of analytical and spectroscopic instruments. This type of knowledge and understanding at the molecular level is fundamentally a strength to gain further knowledge about the medicinal properties of a molecule and to develop skills in discovery and development of molecules as drugs. When a synthetic chemist spends more and more time with interest in learning about medicinal chemistry, the chemist becomes increasingly enthusiastic about learning at the molecular level and the interface of chemistry, biology, and pharmacology, does research with more intuitive involvement in a team for drug discovery and development, and becomes an efficient medicinal chemist. Such gradual transitions in expertise in the profession of a chemist take place quite often. Pharmacy-Background and Synthetic Organic Chemistry Students Learning Medicinal Chemistry: Different Emphases to Acquire KnowledgePharmacy students in undergraduate education learn less about synthetic organic and physical chemistry and, therefore, require in-depth learning on these subjects in graduate education and higher academic programs (Figure 1). In contrast, synthetic organic chemistry students, having little knowledge of pharmaceutical sciences from their undergraduate education, require in-depth studies on the molecular aspects of medicinal properties and branches of pharmaceutical sciences. The efficiency of synthetic organic chemistry enables them to design and take on the challenges of preparing complex molecular skeletons and creating new and patentable chemical space outside of certain types of overpopulated molecular islands. On the other hand, knowledge of pharmaceutical science and medicinal properties enables them to rationally design new molecules with the potential power of expected molecular biological properties to address current specific therapeutic issues and accordingly to plan research projects. The integration of "what and why to synthesize" with pharmaceutical science knowledge and "how to synthesize" with synthetic organic chemistry knowledge is valuable in medicinal chemistry research. With the surge in synthetic organic chemists' efforts to become effective medicinal chemists, in current times the education system emphasizes expertise on both sides─synthetic organic chemistry as well as pharmacy─in the transition to medicinal chemistry for efficient generation of medicinal chemist human resources. Research experts and top leaders in the pharmaceutical industry are involved in medicinal chemistry education, explaining their case studies in the development of new drugs. This collaboration between academia and industry has enhanced the standards of the education and enthusiasm of students with backgrounds in both synthetic organic chemistry and pharmacy for learning medicinal chemistry.Figure 1Figure 1. Expertise-based career transitions to medicinal chemistry.High Resolution ImageDownload MS PowerPoint Slide How Do We Train and Develop Medicinal Chemists?The subject of medicinal chemistry has exceptional uniqueness that can bolster students' enthusiasm for gaining a molecular level understanding of how the physiological processes of the body interact with and respond to pharmaceuticals (exogenous ligands), phytoconstituents, natural foods, and nutrients. Creating enthusiasm in students who have a passion for learning in the field of medicinal chemistry and merging students' intellectual qualities with creativity are important in imparting a high level of education to students. Such students understand the fact that a medicinal chemist makes a significant impact on health science. A medicinal chemist's understanding about the chemical properties of molecules and the interactions of molecules with biological systems plays crucial role in their work at the intersection of chemistry, biology, and pharmacology and contributes to the design, discovery, and development of effective and safe new drugs and therapies. The profession is intellectually stimulating and diverse, requiring continual new learning in rapidly evolving research landscapes, new techniques, advanced instrument technologies, and innovations. Significant involvement of the pharmaceutical industry in education through teaching by medicinal chemistry industry leaders and internship projects is important for students to gain real-life drug discovery research experience. Strategies and Content for Medicinal Chemistry Education for Undergraduate and Graduate Students1)Medicinal chemistry – a molecular level understanding of what an exogeneous molecule can do in the human body as well as what the body can do to the exogeneous molecule.2)Consideration of P3 properties – pharmacodynamics, physicochemical (ADMET-relevant), and pharmacokinetic profile. This requires a change from the conventional "structure–activity relationship" (SAR) to a comprehensive "structure–function relationship" (SFR) approach to all P3 properties of new investigational molecules.3)Critical molecular medicinal insight into the function of drugs, treatment regimens, clinical candidates. Drug Annotations and Patent Highlights published in the Journal of Medicinal Chemistry are useful to consider for teaching.4)Combination therapy to network polypharmacology interference.5)Analysis of molecular mechanisms associated with efficacy versus adverse drug reactions (ADRs) and drug-resistance issues.6)In the design and discovery of novel therapeutic agents, knowledge of "medicinophores" can be introduced. A structural motif that is responsible for improving major medicinal properties of investigated molecules can be termed as a "medicinophore", while a pharmacophore is responsible for ligand-binding to biological macromolecules, and a chromophore represents a molecular part, a group, or an atom in a material that absorbs a particular wavelength of visible light and as a result reflects the color of the material.7)A range of property-focused strategies with innovative thinking and hypothesis-driven design rationale in drug discovery efforts.8)Computer-based predictions: AI, ML, DL, cluster-based analysis, molecular docking, molecular dynamics, various filters for physicochemical properties to create molecular medicinal value, and molecular physicochemical property descriptors.9)Chemical reactions, reagents, processes, logic in chemical (organic) synthesis, retrosynthesis, development of reaction methods and synthetic approaches, access to molecular diversity, and late-stage functionalization.10)Greener syntheses, green chemistry principles, greener reagents, solvents, and methods, and metrics.11)Intellectual property rights and patent law.12)Biophysical studies for evaluation of biological/medicinal properties and in vitro assay protocols, structure–function optimization, and in vivo experiments.13)Knowledge of using advanced scientific (analytical, spectroscopic, and others) instruments in drug discovery.14)Hands-on experience with experiments to gain skills in laboratory and research techniques and practical exposure to course contents.15)Real-life research experience through research projects focusing on particular therapeutic problems and the design, synthesis, and discovery of new bioactive agents or internships for drug discovery R&D experience in the pharmaceutical industry.Author InformationClick to copy section linkSection link copied!Corresponding AuthorSankar K. Guchhait, Department of Medicinal Chemistry National Institute of Pharmaceutical Education and Research (NIPER), S. A. S. Nagar (Mohali), Punjab 160062, India, https://orcid.org/0000-0002-1817-2172, Email: [email protected]NotesViews expressed in this editorial are those of the author and not necessarily the views of the ACS.Cited By Click to copy section linkSection link copied!This article has not yet been cited by other publications.Download PDFFiguresReferences Get e-AlertsGet e-AlertsJournal of Medicinal ChemistryCite this: J. Med. Chem. 2024, XXXX, XXX, XXX-XXXClick to copy citationCitation copied!https://doi.org/10.1021/acs.jmedchem.4c02460Published October 24, 2024 Publication History Received 11 October 2024Published online 24 October 2024Published 2024 by American Chemical Society. This publication is available under these Terms of Use. 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