Structural analysis of dihydrofolate reductases enables rationalization of antifolate binding affinities and suggests repurposing possibilities

The FEBS Journal
Amrisha Bhosle, Nagasuma Chandra

Abstract

Antifolates are competitive inhibitors of dihydrofolate reductase (DHFR), a conserved enzyme that is central to metabolism and widely targeted in pathogenic diseases, cancer and autoimmune disorders. Although most clinically used antifolates are known to be target-specific, some display a fair degree of cross-reactivity with DHFRs from other species. A method that enables identification of determinants of affinity and specificity in target DHFRs from different species and provides guidelines for the design of antifolates is currently lacking. To address this, we first capture the potential druggable space of a DHFR in a sub-structure called the supersite and classify supersites of DHFRs from 56 species into 16 site-types based on pairwise structural similarity. Analysis of supersites across these site-types reveals that DHFRs exhibit varying extents of dissimilarity at structurally equivalent positions in and around the binding site. We are able to explain the pattern of affinities towards chemically diverse antifolates exhibited by DHFRs of different site-types based on these structural differences. We then generate an antifolate-DHFR network by mapping known high affinity antifolates to their respective supersites and use thi...Continue Reading

References

May 1, 1990·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·B I SchweitzerJ R Bertino
Sep 1, 1985·The Journal of Clinical Investigation·B A ChabnerJ Jolivet
Mar 4, 1988·Science·J J TrimbleR C Desrosiers
Apr 1, 1988·Antimicrobial Agents and Chemotherapy·J A KovacsH Masur
Jun 1, 1988·European Journal of Biochemistry·C OefnerF K Winkler
Jan 1, 1980·Annual Review of Biochemistry·S J Benkovic
Jun 1, 1996·Protein Science : a Publication of the Protein Society·F M Huennekens
May 13, 1999·Bioinformatics·V SobolevM Edelman
Nov 2, 1999·Journal of Medicinal Chemistry·S F ChowdhuryI H Gilbert
Dec 11, 1999·Nucleic Acids Research·H M BermanP E Bourne
Jul 12, 2002·Proteins·William S J Valdar
Aug 22, 2003·Organic & Biomolecular Chemistry·Alireza SardarianWorachart Sirawaraporn
Jun 3, 2004·Genome Research·Gavin E CrooksSteven E Brenner
Feb 16, 2006·Current Medicinal Chemistry·D C M Chan, A C Anderson
May 2, 2006·Nature Structural & Molecular Biology·Argyrides ArgyrouJohn S Blanchard
Feb 9, 2007·Nature Biotechnology·Michael J KeiserBrian K Shoichet
Feb 27, 2007·International Journal for Parasitology·Sumalee KamchonwongpaisanYongyuth Yuthavong
Sep 20, 2007·Journal of Chemical Information and Modeling·Michael G LernerHeather A Carlson
Sep 28, 2007·Anti-cancer Agents in Medicinal Chemistry·Aleem GangjeeSonali Kurup
Nov 16, 2007·Proteins·Keunwan Park, Dongsup Kim
Jan 16, 2008·PLoS Computational Biology·Matthew MenkeLenore Cowen
Feb 22, 2008·Anti-cancer Agents in Medicinal Chemistry·Aleem GangjeeSonali Kurup
Nov 15, 2008·Journal of Medicinal Chemistry·Jennifer M BeierleinAmy C Anderson
Dec 19, 2008·BMC Bioinformatics·Kalidas Yeturu, Nagasuma Chandra
Apr 29, 2009·Journal of Computational Chemistry·Garrett M MorrisArthur J Olson
Jun 2, 2009·Current Opinion in Structural Biology·Hitomi Hasegawa, Liisa Holm
Dec 15, 2010·Bioinformatics·Michael E SmootTrey Ideker
May 31, 2011·Expert Opinion on Therapeutic Patents·Dennis L Wright, Amy C Anderson
Jun 15, 2011·Journal of Chemical Information and Modeling·Kalidas Yeturu, Nagasuma Chandra
Aug 16, 2011·Biochimica Et Biophysica Acta·N M GoodeyK C Bagley
Oct 11, 2011·Journal of Cheminformatics·Noel M O'BoyleGeoffrey R Hutchison
Oct 25, 2011·Journal of Chemical Information and Modeling·Jacob D Durrant, J Andrew McCammon
Mar 20, 2012·Nature Methods·Tamás NepuszAlberto Paccanaro
Jun 19, 2012·European Journal of Medicinal Chemistry·Baskar NammalwarWilliam W Barrow
Aug 28, 2012·Drug Resistance Updates : Reviews and Commentaries in Antimicrobial and Anticancer Chemotherapy·Nitzan Gonen, Yehuda G Assaraf

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