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