Combinatorial chemistry involves the rapid synthesis or the computer simulation of a large number of different but structurally related molecules. Combinatorics is a branch of pure mathematics concerning the study of discrete (and usually finite) objects. ... For other uses, see Chemistry (disambiguation). ... Organic synthesis is the construction of organic molecules via chemical processes. ... It has been suggested that simulation software be merged into this article or section. ... 3D (left and center) and 2D (right) representations of the terpenoid molecule atisane. ...

Introduction

Synthesis of molecules in a combinatorial fashion can quickly lead to large numbers of molecules. For example, a molecule with three points of diversity (R₁, R₂, and R₃) can generate possible structures, where , , and are the number of different substituents utilized.

Although combinatorial chemistry has only really been taken up by industry since the 1990s, its roots can be seen as far back as the 1960s when a researcher at Rockefeller University, Bruce Merrifield, started investigating the solid-phase synthesis of peptides. In the 1980s researcher H. Mario Geysen developed this technique further, creating arrays of different peptides on separate supports. Year 1990 (MCMXC) was a common year starting on Monday (link displays the 1990 Gregorian calendar). ... Year 1960 (MCMLX) was a leap year starting on Friday (link will display full calendar) of the Gregorian calendar. ... Founders Hall Rockefeller University is a private university focusing primarily on graduate and postgraduate education research in the biomedical fields, located between 63rd and 68th Streets along York Avenue, on the Upper East Side of Manhattan island in New York City, New York. ... Robert Bruce Merrifield is an American biochemist. ... In chemistry, solid-phase synthesis is a method in which molecules are bound on a bead and synthesized step-by-step in a reactant solution; compared with normal synthesis in a liquid state, it is easier to remove excess reactant or byproduct from the product. ... Peptides (from the Greek πεπτος, digestible), are the family of short molecules formed from the linking, in a defined order, of various α-amino acids. ... Year 1980 (MCMLXXX) was a leap year starting on Tuesday (link displays the 1980 Gregorian calendar). ...

In its modern form, combinatorial chemistry has probably had its biggest impact in the pharmaceutical industry. Researchers attempting to optimize the activity profile of a compound create a 'library' of many different but related compounds. Advances in robotics have led to an industrial approach to combinatorial synthesis, enabling companies to routinely produce over 100,000 new and unique compounds per year (see medicinal chemistry). Pharmacology (in Greek: pharmacon is drug, and logos is science) is the study of how chemical substances interfere with living systems. ... Robotics is the science and technology of robots, their design, manufacture, and application. ... Medicinal or pharmaceutical chemistry is a scientific discipline at the intersection of chemistry and pharmacy involved with designing, synthesizing and developing pharmaceutical drugs. ...

In order to handle the vast number of structural possibilities, researchers often create a 'virtual library', a computational enumeration of all possible structures of a given pharmacophore with all available reactants. Such a library can consist of thousand to millions of 'virtual' compounds. The researcher will select a subset of the 'virtual library' for actual synthesis, based upon various calculations and criteria (see ADME, computational chemistry, and QSAR). A pharmacophore is a three-dimensional substructure of a molecule that carries (phoros) the essential features responsible for a drugs (pharmacon) biological activity. ... A reactant or reagent is any substance initially present in a chemical reaction. ... ADME is an acronym in pharmacokinetics and pharmacology for Absorption, Distribution, Metabolism, and Excretion, and describes the disposition of a pharmaceutical compound within an animal or human body. ... Computational chemistry is a branch of chemistry that uses the results of theoretical chemistry incorporated into efficient computer programs to calculate the structures and properties of molecules and solids, applying these programs to complement the information obtained by actual chemical experiments, predict hitherto unobserved chemical phenomena, and solve related problems. ... QSAR (Quantitative Structure-Activity Relationship, sometimes the A stands also for Affinity=reactivity) is the quantitative correlation of the biological (ecological, toxicological or pharmacological) activity to the structure of chemical compounds, which allows the prediction of the so-called drug efficacy of a structurally related compound. ...

Materials science has applied to the techniques of combinatorial chemistry to the discovery of new materials. This work was pioneered by P.G. Schultz et al. in the mid nineties (Science, 1995, 268: 1738-1740) in the context of luminescent materials obtained by co-deposition of elements on a silicon substrate. Work has been continued by several academic groups as well as companies with large research and development programs (Symyx Technologies, GE, etc). The Materials Science Tetrahedron, which often also includes Characterization at the center Materials science or Materials Engineering is an interdisciplinary field involving the properties of matter and its applications to various areas of science and engineering. ... Peter G. Schultz (born June 23, 1956 in Cincinnati, Ohio) is an American research chemist. ... Symyx Technologies (NASDAQ: SMMX) is a pioneer in the area of combinatorial chemistry applied to heterogeneous catalysis and homogeneous catalysis, polymer formulations, electronic and magnetic materials. ... “GE” redirects here. ...

Diversity-oriented libraries

Even though combinatorial chemistry has been an essential part of early drug discovey for more than two decades, so far only one de novo combinatorail chemistry -synthesized chemical has been approved for clinical use by FDA (a multikinase inhibitor indicated for advanced renal cancer). (newman & Cragg 2007) The analysis of poor succrss rate of the approach has been suggested to connect with the rather limited chemical space covered by products of combinatorial chemistry. When comparing the properties of compounds in combinatorial chemistry libraries to those of approved drugs and natural products, Feher and Schmidt (2003) noted that combinatorial chemistry libraries suffer particularly from the lack of chirality, as well as structure rigidity, both of which are widely regarded as drug-like properties. Even though natural product drug discovery has not probably been the most fashionable trend in pharmaceutical industry in recent times, a large proportion of new chemical entities still is nature-derived compounds, and thus, it has been suggested that effectiveness of combinatorial chemistry could be improved by enhancing the chemical diversity of of screening libraries. As chirality and rigidity are the two most important features distinguishing approved drugs and natural products from compounds in combinatorial chemistry libraries, these are the two issues emphasized in so-called diversity oriented libraries, i.e. compound collections that aim at coverage of the chemical space, instead of just huge number of compounds. Chemical space is the space spanned by all possible (i. ... // Before 20th century, crude and semi-pure extracts of plants, animals, microbes and minerals reprented the only medications available to treat human and domestic animal illnesses. ...

Trivia

In the 8th edition of the International Patent Classification (IPC), which entered into force on January 1, 2006, a special subclass has been created for patent applications and patents related to inventions in the domain of combinatorial chemistry: "C40B". The International Patent Classification (IPC) is a hierarchical patent classification system published by the World Intellectual Property Organization (WIPO). ... is the 1st day of the year in the Gregorian calendar. ... Year 2006 (MMVI) was a common year starting on Sunday of the Gregorian calendar. ... A patent application is a request pending at a patent office for the grant of a patent for the invention described and claimed by that application. ... For other uses, see Patent (disambiguation). ... For the musical form, see Invention (music). ...

See also

• Cheminformatics
• Drug discovery
• High-throughput screening

Cheminformatics (also known as chemoinformatics and chemical informatics) is the use of computer and informational techniques, applied to a range of problems in the field of chemistry. ... In medicine, biotechnology and pharmacology, drug discovery is the process by which drugs are discovered and/or designed. ... High-throughput screening (HTS), is a method for scientific experimentation especially used in drug discovery and relevant to the fields of biology and chemistry. ...

External links

• Journal of Combinatorial Chemistry
• Molecular Diversity
• Combinatorial Chemistry and High Throughput Screening
• Combinatorial Chemistry: an Online Journal
• SmiLib - A free open-source software for combinatorial library enumeration
• GLARE - A free open-source software for combinatorial library design

References

• Newman, D and Cragg, G. Natural produscts as drug over the past 25 years J Nat Prod 70(3): 461-477. (2007).
• Feher, M. and Schmidt, JM. Property Distributions: Differences between Drugs, Natural Products, and Molecules from Combinatorial Chemistry J. Chem. Inf. Comput. Sci., 43 (1), 218 -227, (2003)