Medicinal chemistry
Encyclopedia
Medicinal chemistry and pharmaceutical chemistry are disciplines at the intersection of chemistry
, especially synthetic organic chemistry, and pharmacology
and various other biological specialties, where it is involved with design
, chemical synthesis
and development for market of pharmaceutical agents (drugs
).
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.). Inorganic and organometallic compounds are also useful as drugs (e.g., lithium
and platinum
-based agents such as lithium carbonate
and cis-platin.
In particular, medicinal chemistry in its most common guise—focusing on small organic molecules—encompasses synthetic organic chemistry and aspects of natural products and computational chemistry in close combination with chemical biology
, enzymology and structural 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 of new 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 their structure-activity relationship
s (SAR). Pharmaceutical chemistry is focused on quality aspects of medicines and aims to assure fitness for purpose of medicinal products.
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.
. 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.
s) 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.
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 100's 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.
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., and the preponderance of positions are in discovery, where the net is necessarily cast widest, and most broad synthetic activity occurs.
In discovery 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 more 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.) Hence, although several graduate programs offer Ph.D. and postdoctoral training in medicinal chemistry, the broader education of a top-tier synthetic or physical chemistry graduate program most frequently provides the entry level skills sought for industrial medicinal chemistry.
Chemistry
Chemistry is the science of matter, especially its chemical reactions, but also its composition, structure and properties. Chemistry is concerned with atoms and their interactions with other atoms, and particularly with the properties of chemical bonds....
, especially synthetic organic chemistry, and pharmacology
Pharmacology
Pharmacology is the branch of medicine and biology concerned with the study of drug action. More specifically, it is the study of the interactions that occur between a living organism and chemicals that affect normal or abnormal biochemical function...
and various other biological specialties, where it is involved with design
Drug design
Drug design, also sometimes referred to as rational drug design or structure-based drug design, is the inventive process of finding new medications based on the knowledge of the biological target...
, chemical synthesis
Organic synthesis
Organic synthesis is a special branch of chemical synthesis and is concerned with the construction of organic compounds via organic reactions. Organic molecules can often contain a higher level of complexity compared to purely inorganic compounds, so the synthesis of organic compounds has...
and development for market of pharmaceutical agents (drugs
Medication
A pharmaceutical drug, also referred to as medicine, medication or medicament, can be loosely defined as any chemical substance intended for use in the medical diagnosis, cure, treatment, or prevention of disease.- Classification :...
).
Compounds used as medicines are most often organic compounds, which are often divided into the broad classes of small organic molecules
Small molecule
In the fields of pharmacology and biochemistry, a small molecule is a low molecular weight organic compound which is by definition not a polymer...
(e.g., atorvastatin
Atorvastatin
Atorvastatin , sold by Pfizer under the trade name Lipitor, is a member of the drug class known as statins, used for lowering blood cholesterol. It also stabilizes plaque and prevents strokes through anti-inflammatory and other mechanisms...
, fluticasone
Fluticasone
Fluticasone is a synthetic glucocorticoid.Both the furoate and propionate forms are used as topical anti-inflammatories:*Fluticasone propionate*Fluticasone furoateTreatment of asthma - Fluticasone in combination with Salmeterol - "[]" - aerosol....
, clopidogrel
Clopidogrel
Clopidogrel is an oral, thienopyridine class antiplatelet agent used to inhibit blood clots in coronary artery disease, peripheral vascular disease, and cerebrovascular disease. It is marketed by Bristol-Myers Squibb and Sanofi-Aventis under the trade name Plavix. The drug works by irreversibly...
) and "biologics
Biologics
A biologic is a medicinal product such as a vaccine, blood or blood component, allergenic, somatic cell, gene therapy, tissue, recombinant therapeutic protein, or living cells that are used as therapeutics to treat diseases...
" (infliximab
Infliximab
Infliximab is a monoclonal antibody against tumour necrosis factor alpha . It is used to treat autoimmune diseases. Remicade is marketed by Janssen Biotech, Inc...
, erythropoietin
Erythropoietin
Erythropoietin, or its alternatives erythropoetin or erthropoyetin or EPO, is a glycoprotein hormone that controls erythropoiesis, or red blood cell production...
, insulin glargine
Insulin glargine
Insulin glargine, marketed by Sanofi-Aventis under the name Lantus, is a long-acting basal insulin analogue, given once daily to help control the blood sugar level of those with diabetes. It consists of microcrystals that slowly release insulin, giving a long duration of action of 18 to 26 hours,...
), the latter of which are most often medicinal preparations of proteins (natural and recombinant
Recombinant
Recombinant may refer to:* A recombinant organism - an organism that contains a different combination of alleles from either of its parents.* Recombinant DNA - a form of artificial DNA* Recombinant virus - a virus formed by recombining genetic material...
antibodies, hormones, etc.). Inorganic and organometallic compounds are also useful as drugs (e.g., lithium
Lithium
Lithium is a soft, silver-white metal that belongs to the alkali metal group of chemical elements. It is represented by the symbol Li, and it has the atomic number 3. Under standard conditions it is the lightest metal and the least dense solid element. Like all alkali metals, lithium is highly...
and platinum
Platinum
Platinum is a chemical element with the chemical symbol Pt and an atomic number of 78. Its name is derived from the Spanish term platina del Pinto, which is literally translated into "little silver of the Pinto River." It is a dense, malleable, ductile, precious, gray-white transition metal...
-based agents such as lithium carbonate
Lithium carbonate
Lithium carbonate is a chemical compound of lithium, carbon, and oxygen with the formula Li2CO3. This colorless salt is widely used in the processing of metal oxides and has received attention for its use in psychiatry. It is found in nature as the rare mineral zabuyelite.-Properties:Like almost...
and cis-platin.
In particular, medicinal chemistry in its most common guise—focusing on small organic molecules—encompasses synthetic organic chemistry and aspects of natural products and computational chemistry in close combination with chemical biology
Chemical biology
Chemical biology is a scientific discipline spanning the fields of chemistry and biology that involves the application of chemical techniques and tools, often compounds produced through synthetic chemistry, to the study and manipulation of biological systems. This is a subtle difference from...
, enzymology and structural biology
Structural biology
Structural biology is a branch of molecular biology, biochemistry, and biophysics concerned with the molecular structure of biological macromolecules, especially proteins and nucleic acids, how they acquire the structures they have, and how alterations in their structures affect their function...
, 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 of new chemical entities
New chemical entity
A new chemical entity , or new molecular entity , is, according to the U.S. Food and Drug Administration, a drug that contains no active moiety that has been approved by the FDA in any other application submitted under section 505 of the Federal Food, Drug, and Cosmetic Act.An active moiety is a...
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 their structure-activity relationship
Structure-activity relationship
The structure–activity relationship is the relationship between the chemical or 3D structure of a molecule and its biological activity. The analysis of SAR enables the determination of the chemical groups responsible for evoking a target biological effect in the organism...
s (SAR). Pharmaceutical chemistry is focused on quality aspects of medicines and aims to assure fitness for purpose of medicinal products.
At the biological interface, medicinal chemistry combines to form a set of highly interdisciplinary sciences, setting its organic, physical
Physical chemistry
Physical chemistry is the study of macroscopic, atomic, subatomic, and particulate phenomena in chemical systems in terms of physical laws and concepts...
, and computational
Computational chemistry
Computational chemistry is a branch of chemistry that uses principles of computer science to assist in solving chemical problems. It uses the results of theoretical chemistry, incorporated into efficient computer programs, to calculate the structures and properties of molecules and solids...
emphases alongside biological areas such as biochemistry
Biochemistry
Biochemistry, sometimes called biological chemistry, is the study of chemical processes in living organisms, including, but not limited to, living matter. Biochemistry governs all living organisms and living processes...
, molecular biology
Molecular biology
Molecular biology is the branch of biology that deals with the molecular basis of biological activity. This field overlaps with other areas of biology and chemistry, particularly genetics and biochemistry...
, pharmacognosy
Pharmacognosy
Pharmacognosy is the study of medicines derived from natural sources. The American Society of Pharmacognosy defines pharmacognosy as "the study of the physical, chemical, biochemical and biological properties of drugs, drug substances or potential drugs or drug substances of natural origin as well...
and pharmacology
Pharmacology
Pharmacology is the branch of medicine and biology concerned with the study of drug action. More specifically, it is the study of the interactions that occur between a living organism and chemicals that affect normal or abnormal biochemical function...
, toxicology
Toxicology
Toxicology is a branch of biology, chemistry, and medicine concerned with the study of the adverse effects of chemicals on living organisms...
and veterinary and human medicine
Medicine
Medicine is the science and art of healing. It encompasses a variety of health care practices evolved to maintain and restore health by the prevention and treatment of illness....
; these, with project management
Project management
Project management is the discipline of planning, organizing, securing, and managing resources to achieve specific goals. A project is a temporary endeavor with a defined beginning and end , undertaken to meet unique goals and objectives, typically to bring about beneficial change or added value...
, statistics
Statistics
Statistics is the study of the collection, organization, analysis, and interpretation of data. It deals with all aspects of this, including the planning of data collection in terms of the design of surveys and experiments....
, and pharmaceutical business practices, systematically oversee altering identified chemical agents such that after pharmaceutical formulation
Pharmaceutical formulation
Pharmaceutical formulation, in pharmaceutics, is the process in which different chemical substances, including the active drug, are combined to produce a final medicinal product.-Stages and timeline:...
, they are safe and efficacious, and therefore suitable for use in treatment of disease.
Discovery
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. Initial hits can come from repurposing existing agents toward a new pathologic processes, and from observations of biologic effects of new or existing natural products from bacteria, fungi, plants, 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, 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 chemistryCombinatorial chemistry
Combinatorial chemistry involves the rapid synthesis or the computer simulation of a large number of different but structurally related molecules or materials...
. 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.
Hit to Lead, and Lead Optimization
Further chemistry and analysis is necessary, first to identify and "triage" compounds that do not provide series displaying suitable SAR and chemical characteristics associated with long-term potential for development, then to improve remaining hit series with regard to 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 (pharmacophorePharmacophore
thumb|right|300px|An example of a pharmacophore model.A pharmacophore is an abstract description of molecular features which are necessary for molecular recognition of a ligand by a biological macromolecule....
s) 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.
Process Chemistry and Development
The next through final synthetic chemical stages involve production of lead compound in suitable quantity and quality to allow large scale animal and eventual, extensive human clinical trials. This involves the optimization of the syntheticChemical synthesis
In chemistry, chemical synthesis is purposeful execution of chemical reactions to get a product, or several products. This happens by physical and chemical manipulations usually involving one or more reactions...
route for bulk industrial production, and discovery of the most suitable drug formulation
Formulation
Formulation may refer to:* Clinical formulation* Formulations * Formulation science* Pharmaceutical formulation:** Galenic formulation* Pesticide formulation...
. The former of these is still the bailiwick of medicinal chemistry, the latter brings in the specialization of formulation science
Formulation science
Formulation science is an interdisciplinary subject where knowledge of material science, and physical chemistry, joins with the art of formulating a formulations that can have hyper activity towards a particular action...
(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 100's 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
GMP
GMP may refer to:* Good manufacturing practice, a requirement for manufacturers of foods and medications-Business and organisations:* Gerakan Mansuhkan PPSMI, a coalition of 40 NGOs and political parties in Malaysia...
requirements for material sourcing, handling, and chemistry.
Training in medicinal chemistry
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. 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. Most training regimens include a postdoctoral fellowship period of 2 or more years after receiving a Ph.D. in chemistry. 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., and the preponderance of positions are in discovery, where the net is necessarily cast widest, and most broad synthetic activity occurs.
In discovery 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 more 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.) Hence, although several graduate programs offer Ph.D. and postdoctoral training in medicinal chemistry, the broader education of a top-tier synthetic or physical chemistry graduate program most frequently provides the entry level skills sought for industrial medicinal chemistry.
See also
- Drug designDrug designDrug design, also sometimes referred to as rational drug design or structure-based drug design, is the inventive process of finding new medications based on the knowledge of the biological target...
- Drug metabolismDrug metabolismDrug metabolism is the biochemical modification of pharmaceutical substances by living organisms, usually through specialized enzymatic systems. This is a form of xenobiotic metabolism. Drug metabolism often converts lipophilic chemical compounds into more readily excreted polar products...
- Enzyme inhibitorEnzyme inhibitorAn enzyme inhibitor is a molecule that binds to enzymes and decreases their activity. Since blocking an enzyme's activity can kill a pathogen or correct a metabolic imbalance, many drugs are enzyme inhibitors. They are also used as herbicides and pesticides...
s - Galenic formulationGalenic formulationGalenic formulation deals with the principles of preparing and compounding medicines in order to optimize their absorption. Galenic formulation is named after Claudius Galen, a 2nd Century AD Greek physician, who codified the preparation of drugs using multiple ingredients...
- Inverse benefit lawInverse benefit lawThe Inverse Benefit Law states that the ratio of benefits to harms among patients taking new drugs tends to vary inversely with how extensively a drug is marketed...
- Important publications in medicinal chemistry
- Medical biologyMedical biologyMedical biology is a field of biology that has practical applications in medicine, health care and laboratory diagnostics. It includes many biomedical disciplines and areas of specialty that typically contain the "bio-" prefix such as:...
- Medical physicsMedical physicsMedical physics is the application of physics to medicine. It generally concerns physics as applied to medical imaging and radiotherapy, although a medical physicist may also work in many other areas of healthcare...
- Molecular ConceptorMolecular ConceptorThe Molecular Conceptor Learning Series, produced by Synergix Ltd, is an interactive computer-based learning suite that teaches the principles and techniques used in everyday drug discovery...
- Pharmaceutical companyPharmaceutical companyThe pharmaceutical industry develops, produces, and markets drugs licensed for use as medications. Pharmaceutical companies are allowed to deal in generic and/or brand medications and medical devices...
- PharmacodynamicsPharmacodynamicsPharmacodynamics is the study of the biochemical and physiological effects of drugs on the body or on microorganisms or parasites within or on the body and the mechanisms of drug action and the relationship between drug concentration and effect...
- PharmacognosyPharmacognosyPharmacognosy is the study of medicines derived from natural sources. The American Society of Pharmacognosy defines pharmacognosy as "the study of the physical, chemical, biochemical and biological properties of drugs, drug substances or potential drugs or drug substances of natural origin as well...
- PharmacokineticsPharmacokineticsPharmacokinetics, sometimes abbreviated as PK, is a branch of pharmacology dedicated to the determination of the fate of substances administered externally to a living organism...
- PharmacologyPharmacologyPharmacology is the branch of medicine and biology concerned with the study of drug action. More specifically, it is the study of the interactions that occur between a living organism and chemicals that affect normal or abnormal biochemical function...
- PharmacophorePharmacophorethumb|right|300px|An example of a pharmacophore model.A pharmacophore is an abstract description of molecular features which are necessary for molecular recognition of a ligand by a biological macromolecule....
- Xenobiotic metabolismXenobiotic metabolismXenobiotic metabolism is the set of metabolic pathways that modify the chemical structure of xenobiotics, which are compounds foreign to an organism's normal biochemistry, such as drugs and poisons...
External links
- American Chemical Society Division of Medicinal Chemistry
- European Federation for Medicinal Chemistry
- A guide to drug discovery: The role of the medicinal chemist in drug discovery — then and now, an article published in Nature Reviews Drug Discovery that gives a historical perspective of the field and insight to future directions
- Find here the medicinal chemistry summary of the pharmaceutical drug discovery patent
Scientific journals
- MedChemCommMedChemCommMedChemComm is a peer-reviewed scientific journal publishing original research and review articles on all aspects of medicinal chemistry. It is published monthly by the Royal Society of Chemistry...
(MedChemComm Home page) - Future Medicinal Chemistry
- ChemmedchemChemmedchemChemMedChem is a monthly peer-reviewed medicinal chemistry journal. It is co-owned by the 14 European chemical society members of ChemPubSoc Europe and is published by Wiley-VCH. Its 2010 impact factor is 3.306...
(ChemMedChem current issue page) - Journal of Medicinal ChemistryJournal of Medicinal ChemistryThe Journal of Medicinal Chemistry , is a peer-reviewed scientific journal, published since 1959 by the American Chemical Society...
(table of contents) - Current Medicinal Chemistry
- European Journal of Medicinal Chemistry (table of contents)