Editing Combinatorial chemistry (section)

==Introduction==
The basic principle of combinatorial chemistry is to prepare [[compound library|libraries]] of a very large number of compounds and identify those which are useful as potential drugs or agrochemicals. This relies on [[high-throughput screening]] which is capable of assessing the output at sufficient scale.<ref name=Warr1997>{{cite journal |doi=10.1021/ci9601426 |title=Combinatorial Chemistry and Molecular Diversity. An Overview |date=1997 |last1=Warr |first1=Wendy A. |journal=Journal of Chemical Information and Computer Sciences |volume=37 |pages=134–140 |url=http://www-personal.engin.umich.edu:80/~wildd/che697/warr97.pdf |url-status=dead |archive-url=https://web.archive.org/web/20040218214851id_/http://www-personal.engin.umich.edu:80/~wildd/che697/warr97.pdf |archive-date=2004-02-18 }}</ref>

Although combinatorial chemistry has only really been taken up by industry since the 1990s,<ref>{{cite journal |doi=10.13040/IJPSR.0975-8232.4(7).2502-16 |doi-access=free |date=2013 |journal=International Journal of Pharmaceutical Sciences and Research |volume=4 |issue=7 |title=Combinatorial chemistry: a review |first1=Anas |last1=Rasheed |first2=Rumana |last2=Farhat }}</ref> 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 [[peptide]]s. Synthesis of peptides in a [[combinatorial]] fashion quickly leads to large numbers of molecules. Using the twenty natural [[amino acids]], for example, in a [[tripeptide]] creates 8,000 (20<sup>3</sup>) possibilities. Solid-phase methods for small molecules were later introduced and Furka devised a "split and mix" approach<ref name=Warr1997/><ref name=Furka>{{cite journal |doi=10.1016/S1359-6446(02)00001-6 |title=Combinatorial chemistry: 20 years on… |date=2002 |last1=Furka |first1=Árpád |journal=Drug Discovery Today |volume=7 |issue=1 |pages=1–4 |pmid=11790588 }}</ref>

In its modern form, combinatorial chemistry has probably had its biggest impact in the [[pharmaceutical]] industry.<ref>{{Cite web|url=https://pubs.acs.org/subscribe/archive/tcaw/11/i01/html/01lesney.html|title=Concocting combinatorials: Chemistry in drug development|last=Lesney|first=Mark S.|date=2002|access-date=October 19, 2018}}</ref> Researchers attempting to optimize the activity profile of a compound create a 'library' of many different but related compounds.<ref>{{Cite book |last=Dolle |first=Roland |title=Historical overview of chemical library design |publisher=in Zhou, J.Z. (ed.), Chemical Library Design, Methods in Molecular Biology, Springer, 2011, Chapter 1, pp. 3-25 |year=2011}}</ref><ref>{{Cite journal |last1=Podlewska |first1=S. |last2=Czarnecki |first2=W.M. |last3=Kafel |first3=R. |last4=Bojarski |first4=A.J. |date=2017 |title=Creating the New from the Old: Combinatorial Libraries Generation with Machine-Learning-Based Compound Structure Optimization |journal=J. Chem. Inf. Modeling |volume=57 |issue=2 |pages=133–147|doi=10.1021/acs.jcim.6b00426 |pmid=28158942 }}</ref> 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.<ref>Jeffrey W. Noonan et al. "Advancing Parallel Solution Phase Library Synthesis through Efficient Purification, Quantitation, and Characterization Techniques" {{doi|10.1016/S1535-5535-03-00017-0}} Journal of Laboratory Automation, 48 (1992) 3789].</ref>

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 [[reactant]]s.<ref>E. V.Gordeeva et al. "COMPASS program - an original semi-empirical approach to computer-assisted synthesis" {{doi|10.1016/S0040-4020(01)92270-7}} Tetrahedron, 48 (1992) 3789].</ref>  Such a library can consist of thousands 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 [[Quantitative structure–activity relationship|QSAR]]). 

In 1996, at Parke-Davis Pharmaceutical Research, scientist Anthony Czarnik directed research and reported the first use of automation in synthesizing compound libraries. As the founding editor of the American Chemical Society's Journal of Combinatorial Chemistry, he also led research into RFID tags for targeted sorting in compound library synthesis.<ref>{{cite web |last1=DeWitt |first1=Sheila Hobbs |last2=Czarnik |first2=Anthony W. |title=Combinatorial Organic Synthesis Using Parke-Davis's DIVERSOMER Method |url=https://pubs.acs.org/doi/pdf/10.1021/ar950209v |website=Accounts of Chemical Research |pages=114–122 |language=en |doi=10.1021/ar950209v |date=13 March 1996}}</ref><ref>{{cite news |last1=Herpin |first1=Timothy F |last2=Morton |first2=George C |title=Directed Sorting Approach for the Synthesis of Large Combinatorial Libraries of Discrete Compounds |url=https://www.researchgate.net/publication/8920038_Directed_Sorting_Approach_for_the_Synthesis_of_Large_Combinatorial_Libraries_of_Discrete_Compounds |work=Methods in Enzymology |date=1 January 2003 |pages=75–99}}</ref>