For our Pharm.D. students, medicinal chemistry is integrated with pharmacology to present a coherent picture of the principles of drug action. Pharmacology mainly deals with drug action at the cellular, tissue/organ and organism levels. Medicinal chemistry focuses on the molecular aspects of drug action: interactions with the drug targets from both the drug and the target point of view, the relationship of drug chemical structure to drug action and the effects of metabolism on the drug structure and hence its action.
In 1999, in response to the significant growth of the College of Pharmacy under previous Dean Ara G. Paul, then Dean George L. Kenyon initiated a process of departmentalization of the College of Pharmacy. Prof. James K. Coward was the first Chair of the Department of Medicinal Chemistry and Director of the Med Chem IDP. The Department of Medicinal Chemistry is the administrative component of the College of Pharmacy that oversees the Medicinal Chemistry faculty, research scientists and postdoctoral fellows (e.g., recruitment, mentoring, evaluation), has responsibility for the medicinal chemistry Pharm.D. and Ph.D. courses and seminar program, and coordinates the participation of medicinal chemistry faculty in College-level committees and other administrative duties.
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Medicinal or pharmaceutical chemistry is a scientific discipline at the intersection of chemistry and pharmacy involved with designing and developing pharmaceutical drugs. Medicinal chemistry involves the identification, synthesis and development of new chemical entities suitable for therapeutic use. It also includes the study of existing drugs, their biological properties, and their quantitative structure-activity relationships (QSAR).[1][2]
Compounds used as medicines are most often organic compounds, which are often divided into the broad classes of small organic molecules (e.g., atorvastatin, fluticasone, clopidogrel) and "biologics" (infliximab, erythropoietin, insulin glargine), the latter of which are most often medicinal preparations of proteins (natural and recombinant antibodies, hormones etc.). Medicines can also be inorganic and organometallic compounds, commonly referred to as metallodrugs (e.g., platinum, lithium and gallium-based agents such as cisplatin, lithium carbonate and gallium nitrate, respectively). The discipline of Medicinal Inorganic Chemistry investigates the role of metals in medicine (metallotherapeutics), which involves the study and treatment of diseases and health conditions associated with inorganic metals in biological systems. There are several metallotherapeutics approved for the treatment of cancer (e.g., contain Pt, Ru, Gd, Ti, Ge, V, and Ga), antimicrobials (e.g., Ag, Cu, and Ru), diabetes (e.g., V and Cr), broad-spectrum antibiotic (e.g., Bi), bipolar disorder (e.g., Li).[3][4] Other areas of study include: metallomics, genomics, proteomics, diagnostic agents (e.g., MRI: Gd, Mn; X-ray: Ba, I) and radiopharmaceuticals (e.g., 99mTc for diagnostics, 186Re for therapeutics).
At the biological interface, medicinal chemistry combines to form a set of highly interdisciplinary sciences, setting its organic, physical, and computational emphases alongside biological areas such as biochemistry, molecular biology, pharmacognosy and pharmacology, toxicology and veterinary and human medicine; these, with project management, statistics, and pharmaceutical business practices, systematically oversee altering identified chemical agents such that after pharmaceutical formulation, they are safe and efficacious, and therefore suitable for use in treatment of disease.
Discovery is the identification of novel active chemical compounds, often called "hits", which are typically found by assay of compounds for a desired biological activity.[6] Initial hits can come from repurposing existing agents toward a new pathologic processes,[7] and from observations of biologic effects of new or existing natural products from bacteria, fungi,[8] plants,[9] etc. In addition, hits also routinely originate from structural observations of small molecule "fragments" bound to therapeutic targets (enzymes, receptors, etc.), where the fragments serve as starting points to develop more chemically complex forms by synthesis. Finally, hits also regularly originate from en-masse testing of chemical compounds against biological targets using biochemical or chemoproteomics assays, where the compounds may be from novel synthetic chemical libraries known to have particular properties (kinase inhibitory activity, diversity or drug-likeness, etc.), or from historic chemical compound collections or libraries created through combinatorial chemistry. While a number of approaches toward the identification and development of hits exist, the most successful techniques are based on chemical and biological intuition developed in team environments through years of rigorous practice aimed solely at discovering new therapeutic agents.
Further chemistry and analysis is necessary, first to identify the "triage" compounds that do not provide series displaying suitable SAR and chemical characteristics associated with long-term potential for development, then to improve the remaining hit series concerning the desired primary activity, as well as secondary activities and physiochemical properties such that the agent will be useful when administered in real patients. In this regard, chemical modifications can improve the recognition and binding geometries (pharmacophores) of the candidate compounds, and so their affinities for their targets, as well as improving the physicochemical properties of the molecule that underlie necessary pharmacokinetic/pharmacodynamic (PK/PD), and toxicologic profiles (stability toward metabolic degradation, lack of geno-, hepatic, and cardiac toxicities, etc.) such that the chemical compound or biologic is suitable for introduction into animal and human studies.[citation needed]
The final synthetic chemistry stages involve the production of a lead compound in suitable quantity and quality to allow large scale animal testing, and then human clinical trials. This involves the optimization of the synthetic route for bulk industrial production, and discovery of the most suitable drug formulation. The former of these is still the bailiwick of medicinal chemistry, the latter brings in the specialization of formulation science (with its components of physical and polymer chemistry and materials science). The synthetic chemistry specialization in medicinal chemistry aimed at adaptation and optimization of the synthetic route for industrial scale syntheses of hundreds of kilograms or more is termed process synthesis, and involves thorough knowledge of acceptable synthetic practice in the context of large scale reactions (reaction thermodynamics, economics, safety, etc.). Critical at this stage is the transition to more stringent GMP requirements for material sourcing, handling, and chemistry.[citation needed]
The synthetic methodology employed in medicinal chemistry is subject to constraints that do not apply to traditional organic synthesis. Owing to the prospect of scaling the preparation, safety is of paramount importance. The potential toxicity of reagents affects methodology.[5][10]
The structures of pharmaceuticals are assessed in many ways, in part as a means to predict efficacy, stability, and accessibility. Lipinski's rule of five focus on the number of hydrogen bond donors and acceptors, number of rotatable bonds, surface area, and lipophilicity. Other parameters by which medicinal chemists assess or classify their compounds are: synthetic complexity, chirality, flatness, and aromatic ring count.
Structural analysis of lead compounds is often performed through computational methods prior to actual synthesis of the ligand(s). This is done for a number of reasons, including but not limited to: time and financial considerations (expenditure, etc.). Once the ligand of interest has been synthesized in the laboratory, analysis is then performed by traditional methods (TLC, NMR, GC/MS, and others).[5]
Graduate level programs in medicinal chemistry can be found in traditional medicinal chemistry or pharmaceutical sciences departments, both of which are traditionally associated with schools of pharmacy, and in some chemistry departments. However, the majority of working medicinal chemists have graduate degrees (MS, but especially Ph.D.) in organic chemistry, rather than medicinal chemistry,[11] and the preponderance of positions are in research, where the net is necessarily cast widest, and most broad synthetic activity occurs.
In research of small molecule therapeutics, an emphasis on training that provides for breadth of synthetic experience and "pace" of bench operations is clearly present (e.g., for individuals with pure synthetic organic and natural products synthesis in Ph.D. and post-doctoral positions, ibid.). In the medicinal chemistry specialty areas associated with the design and synthesis of chemical libraries or the execution of process chemistry aimed at viable commercial syntheses (areas generally with fewer opportunities), training paths are often much more varied (e.g., including focused training in physical organic chemistry, library-related syntheses, etc.).
The Department of Medicinal Chemistry is part of the highly collaborative, interdisciplinary School of Pharmacy. Medicinal Chemistry is a discipline with a traditional focus on organic synthetic chemistry with the broad goals of drug discovery and optimization. The Department of Medicinal Chemistry has always departed somewhat from this tradition given the focus of many of its faculty on the research areas of mechanistic drug metabolism, toxicology, and bioanalytical chemistry.
Research in medicinal chemistry encompasses a broad spectrum of activities including studies pursuant to investigations of the interaction of both drugs and toxic substances with biological systems, and the relationship of chemical structure and dynamics to biological effect and function. In recent years research activities in the Department have been broadened further by the addition of several faculty members with expertise in the areas of biological mass spectrometry and biophysical virology. 152ee80cbc
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