Expanding medicinal chemistry into 3D space: metallofragments as 3D scaffolds for fragment-based drug discovery.

Chemical Science
Christine N MorrisonSeth M Cohen

Abstract

Fragment-based drug discovery (FBDD) is a powerful strategy for the identification of new bioactive molecules. FBDD relies on fragment libraries, generally of modest size, but of high chemical diversity. Although good chemical diversity in FBDD libraries has been achieved in many respects, achieving shape diversity - particularly fragments with three-dimensional (3D) structures - has remained challenging. A recent analysis revealed that >75% of all conventional, organic fragments are predominantly 1D or 2D in shape. However, 3D fragments are desired because molecular shape is one of the most important factors in molecular recognition by a biomolecule. To address this challenge, the use of inert metal complexes, so-called 'metallofragments' (mFs), to construct a 3D fragment library is introduced. A modest library of 71 compounds has been prepared with rich shape diversity as gauged by normalized principle moment of inertia (PMI) analysis. PMI analysis shows that these metallofragments occupy an area of fragment space that is unique and highly underrepresented when compared to conventional organic fragment libraries that are comprised of orders of magnitude more molecules. The potential value of this metallofragment library is de...Continue Reading

References

May 28, 2003·Journal of Chemical Information and Computer Sciences·Wolfgang H B Sauer, Matthias K Schwarz
Oct 8, 2003·Current Pharmaceutical Design·M GalanskiB K Keppler
Oct 14, 2003·Drug Discovery Today·Miles CongreveHarren Jhoti
Jan 24, 2004·Reviews of Physiology, Biochemistry and Pharmacology·H WegeleJ Buchner
Apr 2, 2005·Journal of Medicinal Chemistry·Philip J HajdukStephen W Fesik
Jul 19, 2005·Drug Discovery Today·Robin A E CarrDavid C Rees
Aug 17, 2005·Current Topics in Medicinal Chemistry·Ansgar SchuffenhauerEdgar Jacoby
Feb 2, 2006·Journal of the American Chemical Society·Anna F A PeacockPeter J Sadler
Apr 13, 2006·Journal of the American Chemical Society·Ella Lai-Ming WongChi-Ming Che
Feb 22, 2008·Proceedings of the National Academy of Sciences of the United States of America·James TsaiGideon Bollag
May 7, 2008·Journal of Medicinal Chemistry·Miles CongreveAndrew J Woodhead
Oct 16, 2009·Journal of Medicinal Chemistry·Frank LoveringChristine Humblet
Mar 13, 2010·Current Opinion in Chemical Biology·Anthony G CoyneChris Abell
Sep 25, 2010·Nature Communications·Warren R J D GallowayDavid R Spring
Oct 14, 2010·Angewandte Chemie·Clotilde PolicarAlexandre Dazzi
Nov 17, 2010·Journal of Medicinal Chemistry·Gilles GasserNils Metzler-Nolte
Apr 13, 2011·Proceedings of the National Academy of Sciences of the United States of America·Alvin W HungDamian W Young
Nov 15, 2011·Trends in Microbiology·Patrice NordmannDavid M Livermore
Jun 16, 2012·Biochemistry·Duncan E ScottChris Abell
Jun 27, 2012·Dalton Transactions : an International Journal of Inorganic Chemistry·Sebastian BlanckEric Meggers
Sep 27, 2012·Journal of Chemical Information and Modeling·Nicholas C FirthJulian Blagg
Aug 3, 2013·Drug Discovery Today·Andrew D MorleyPaul G Wyatt
Jan 30, 2014·Chemical Biology & Drug Design·Matteo AldeghiAh Wing Edith Chan
Feb 25, 2014·Current Opinion in Chemical Biology·Markus Dörr, Eric Meggers
Dec 1, 2004·Drug Discovery Today. Technologies·Christopher A Lipinski
Jul 30, 2015·Molecular Cancer Research : MCR·Lisa M ButlerPaul Workman
Aug 31, 2016·Future Medicinal Chemistry·Joshua MeyersNathan Brown
Jul 12, 2017·Cancer Cell·Julian Blagg, Paul Workman
Jul 18, 2017·Accounts of Chemical Research·Seth M Cohen
Sep 28, 2017·Journal of the American Chemical Society·Kevin M KnopfJustin J Wilson
Apr 7, 2018·Drugs·Young-A Heo
Aug 24, 2018·Journal of Medicinal Chemistry·Tristan A ReekieMichael Kassiou
Sep 8, 2018·Chemical Reviews·Allie Y ChenSeth M Cohen
Oct 24, 2018·Journal of Medicinal Chemistry·Cy V CredilleSeth M Cohen
Dec 21, 2018·ACS Chemical Biology·Rachel M VadenBryan E Welm
Jan 22, 2019·Dalton Transactions : an International Journal of Inorganic Chemistry·Amandeep SinghVipan Kumar

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Citations

Jul 3, 2021·Pharmaceutics·Alexandra-Cristina Munteanu, Valentina Uivarosi
Mar 25, 2020·Chemical Science·Angelo FreiMark A T Blaskovich
Jun 24, 2020·Chemical Communications : Chem Comm·Xuezhao LiChunying Duan
Jul 18, 2020·Journal of Biological Inorganic Chemistry : JBIC : a Publication of the Society of Biological Inorganic Chemistry·Eduardo H S SousaJosé J G Moura
Sep 20, 2020·Proceedings of the National Academy of Sciences of the United States of America·Ishika SahaPatrick G Harran
Oct 9, 2020·Dalton Transactions : an International Journal of Inorganic Chemistry·Raphael E F de PaivaFernando R G Bergamini
Nov 20, 2020·Advances and Applications in Bioinformatics and Chemistry : AABC·Woong-Hee ShinDaisuke Kihara
Nov 25, 2020·Chemistry : a European Journal·Angelo FreiMark A T Blaskovich
Nov 27, 2020·Metallomics : Integrated Biometal Science·Garrick CentolaAngela Wilks
May 25, 2021·Journal of Chemical Information and Modeling·Alan E BilslandJustin Bower
Jun 3, 2021·Biomedicines·Damiano CirriTiziano Marzo
Jun 15, 2021·Chemical Science·Elizabeth J AnthonyZijin Zhang
Apr 20, 2021·Chemical Communications : Chem Comm·Kathleen E ProsserSeth M Cohen
Jul 13, 2021·Biological Chemistry·Jeannine Hess
Sep 5, 2020·Accounts of Chemical Research·Aaron R WegenerJohn A Gladysz
Jun 20, 2020·ACS Medicinal Chemistry Letters·Kathleen E ProsserSeth M Cohen
Sep 24, 2021·Chemistry : a European Journal·Monika CziferszkyRonald Gust

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Methods Mentioned

BETA
thermal shift
X-ray

Software Mentioned

Molecular Operating Environment
ZINC

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