Editing Combinatorial chemistry (section)

==Diversity-oriented libraries==
Even though combinatorial chemistry has been an essential part of early drug discovery for more than two decades, so far only one de novo combinatorial chemistry-synthesized chemical has been approved for clinical use by FDA ([[sorafenib]], a multikinase inhibitor indicated for advanced renal cancer).<ref>D. Newman and G. Cragg "Natural Products as Sources of New Drugs over the Last 25 Years" [https://dx.doi.org/10.1021/np068054v J Nat Prod 70 (2007) 461]</ref> The analysis of the poor success rate of the approach has been suggested to connect with the rather limited [[chemical space]] covered by products of combinatorial chemistry.<ref name="pubs.acs.org">M. Feher and J. M. Schmidt "Property Distributions: Differences between Drugs, Natural Products, and Molecules from Combinatorial Chemistry" {{doi|10.1021/ci0200467}} J. Chem. Inf. Comput. Sci., 43 (2003) 218]</ref> When comparing the properties of compounds in combinatorial chemistry libraries to those of approved drugs and natural products, Feher and Schmidt<ref name="pubs.acs.org"/>  noted that combinatorial chemistry libraries suffer particularly from the lack of [[Chirality (chemistry)|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 the pharmaceutical industry in recent times,<ref name=Warr1997/> a large proportion of new chemical entities still are nature-derived compounds,<ref>{{Cite journal |last1=Cordier |first1=C. |last2=Morton |first2=D. |last3=Murrison |first3=S. |last4=Nelson |first4=A. |last5=O'Leary-Steele |first5=C. |date=2008 |title=Natural products as an inspiration in the diversity-oriented synthesis of bioactive compound libraries |journal=Nat. Prod. Rep. |volume=25 |issue=4 |pages=719–737 |doi=10.1039/B706296F|pmid=18663392 |pmc=2496956 |s2cid=15697405 }}</ref><ref>{{Cite journal |last1=de Sousa Luis |first1=J.A. |last2=Costa Barros |first2=R.P. |last3=de Sousa |first3=N.F. |last4=Muratov |first4=E. |last5=Scotti |first5=L. |last6=Scotti |first6=M.T. |date=2021 |title=Virtual screening of natural products database |journal=Mini-Rev. Med. Chem. |volume=21 |issue=18 |pages=2657–2730 |doi=10.2174/1389557520666200730161549|pmid=32744975 |s2cid=220965407 }}</ref><ref>{{Cite journal |last=Harvey |first=A.L. |date=2008 |title=Natural products in drug discovery |journal=Drug Discov. Today |volume=13 |issue=19–20 |pages=894–901 |doi=10.1016/j.drudis.2008.07.004|pmid=18691670 }}</ref><ref>{{Cite journal |last1=Kaiser |first1=M. |last2=Wetzel |first2=S. |last3=Kumar |first3=K. |last4=Waldmann |first4=H. |date=2008 |title=Biology-inspired synthesis of compound libraries |journal=Cell. Mol. Life Sci. |volume=65 |issue=7–8 |pages=1186–1201 |doi=10.1007/s00018-007-7492-1|pmid=18193390 |s2cid=22601514 |doi-access=free |pmc=11131879 }}</ref> and thus, it has been suggested that effectiveness of combinatorial chemistry could be improved by enhancing the chemical diversity of screening libraries.<ref>Su QB, Beeler AB, Lobkovsky E, Porco JA, Panek JS "Stereochemical diversity through cyclodimerization: Synthesis of polyketide-like macrodiolides." Org Lett 2003, 5:2149-2152.</ref> 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 numbers of compounds.<ref>{{Cite journal |last1=Medina-Franco |first1=J.L. |last2=Martínez-Mayorga |first2=K. |last3=Giulianotti |first3=M.A. |last4=Houghten |first4=R.A. |last5=Pinilla |first5=C. |date=2008 |title=Visualization of the chemical space in drug discovery |journal=Curr Comput-Aided Drug Des |volume=4 |issue=4 |pages=322–333 |doi=10.2174/157340908786786010 }}</ref><ref>{{Cite journal |last1=Rosén |first1=J. |last2=Gottfries |first2=J. |last3=Muresan |first3=S. |last4=Backlund |first4=A. |last5=Oprea |first5=T.I. |date=2009 |title=Novel Chemical Space Exploration via Natural Products |journal=J. Med. Chem. |volume=52 |issue=7 |pages=1953–1962 |doi=10.1021/jm801514w|pmid=19265440 |pmc=2696019 }}</ref><ref>{{Cite journal |last1=Lachance |first1=H. |last2=Wetzel |first2=S. |last3=Kumar |first3=K. |last4=Waldmann |first4=H. |date=2012 |title=Charting, Navigating, and Populating Natural Product Chemical Space for Drug Discovery |journal=J. Med. Chem. |volume=55 |issue=13 |pages=5989–6001 |doi=10.1021/jm300288g|pmid=22537178 }}</ref><ref>{{Cite journal |last1=Reymond |first1=J.-L. |last2=Awale |first2=M. |date=2012 |title=Exploring Chemical Space for Drug Discovery Using the Chemical Universe Database |journal=ACS Chem. Neurosci. |volume=3 |issue=9 |pages=649–657 |doi=10.1021/cn3000422|pmid=23019491 |pmc=3447393 }}</ref><ref>{{Cite book |last=Medina-Franco |first=J.L. |title=Chemoinformatic characterization of the chemical space and molecular diversity of compound libraries, in Diversity-Oriented Synthesis: Basics and Applications in Organic Synthesis, Drug Discovery, and Chemical Biology, Trabocchi, A.; Ed., Chapter 10, 2013, 325-352 |publisher=John Wiley & Sons, Inc. |year=2013}}</ref><ref>{{Cite book |last1=Klein |first1=R. |title=Combinatorial Chemistry Library Design, in, Plant Chemical Biology, Audenaert, D.; Overvoorde, P.; Eds. |last2=Lindell |first2=S.D. |publisher=John Wiley & Sons, Inc. |year=2014 |location=New Jersey |pages=40–63}}</ref>