Medicinal orpharmaceutical chemistry is a scientific discipline at the intersection ofchemistry andpharmacy involved withdesigning and developingpharmaceuticaldrugs. Medicinal chemistry involves the identification, synthesis and development ofnew chemical entities suitable for therapeutic use. It also includes the study of existing drugs, their biological properties, and theirquantitative structure-activity relationships (QSAR).[1][2]
Medicinal chemistry is a highly interdisciplinary science combiningorganic chemistry withbiochemistry,computational chemistry,pharmacology,molecular biology,statistics, andphysical chemistry.
Compounds used as medicines are most oftenorganic compounds, which are often divided into the broad classes ofsmall 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 andrecombinantantibodies,hormones etc.). Medicines can also beinorganic andorganometallic compounds, commonly referred to as metallodrugs (e.g.,platinum,lithium andgallium-based agents such ascisplatin,lithium carbonate andgallium nitrate, respectively). The discipline of Medicinal Inorganic Chemistry investigates the role ofmetals in medicine metallotherapeutics, which involves the study and treatment of diseases and health conditions associated withinorganic 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) andradiopharmaceuticals (e.g.,99mTc for diagnostics,186Re for therapeutics).
In particular, medicinal chemistry in its most common practice—focusing on small organic molecules—encompassessynthetic organic chemistry and aspects of natural products andcomputational chemistry in close combination withchemical biology,enzymology andstructural biology, together aiming at the discovery and development of new therapeutic agents. Practically speaking, it involves chemical aspects of identification, and then systematic, thorough synthetic alteration ofnew chemical entities to make them suitable for therapeutic use. It includes synthetic and computational aspects of the study of existing drugs and agents in development in relation to their bioactivities (biological activities and properties), i.e., understanding theirstructure–activity relationships (SAR). Pharmaceutical chemistry is focused on quality aspects of medicines and aims to assure fitness for purpose of medicinal products.[5]
At the biological interface, medicinal chemistry combines to form a set of highly interdisciplinary sciences, setting its organic,physical, andcomputational emphases alongside biological areas such asbiochemistry,molecular biology,pharmacognosy andpharmacology,toxicology andveterinary and humanmedicine; these, withproject management,statistics, and pharmaceutical business practices, systematically oversee altering identified chemical agents such that afterpharmaceutical formulation, they are safe andefficacious, 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 desiredbiological 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 existingnatural 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 fromen-masse testing of chemical compounds against biological targets using biochemical orchemoproteomics assays, where the compounds may be from novel syntheticchemical libraries known to have particular properties (kinase inhibitory activity, diversity or drug-likeness, etc.), or from historic chemical compound collections or libraries created throughcombinatorial 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 necessarypharmacokinetic/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 humanclinical trials. This involves the optimization of thesynthetic route for bulk industrial production, and discovery of the most suitable drugformulation. The former of these is still the bailiwick of medicinal chemistry, the latter brings in the specialization offormulation 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 termedprocess 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 stringentGMP 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 traditionalorganic 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]
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Medicinal chemistry is by nature an interdisciplinary science, and practitioners have a strong background in organic chemistry, which must eventually be coupled with a broad understanding of biological concepts related to cellular drug targets.[11] Scientists in medicinal chemistry work are principally industrial scientists (but see following), working as part of an interdisciplinary team that uses their chemistry abilities, especially, their synthetic abilities, to use chemical principles to design effective therapeutic agents. The length of training is intense, with practitioners often required to attain a 4-year bachelor's degree followed by a 4–6 year Ph.D. in organic chemistry. Most training regimens also include a postdoctoral fellowship period of 2 or more years after receiving a Ph.D. in chemistry, making the total length of training range from 10 to 12 years of college education.[12] However, employment opportunities at the Master's level also exist in the pharmaceutical industry, and at that and the Ph.D. level there are further opportunities for employment in academia and government.
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,[13] 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.).
As such, most entry-level workers in medicinal chemistry, especially in the U.S., do not have formal training in medicinal chemistry but receive the necessary medicinal chemistry and pharmacologic background after employment—at entry into their work in a pharmaceutical company, where the company provides its particular understanding or model of "medichem" training through active involvement in practical synthesis on therapeutic projects. (The same is somewhat true of computational medicinal chemistry specialties, but not to the same degree as in synthetic areas.)
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