Rational Design of Novel Allosteric Dihydrofolate Reductase Inhibitors Showing Antibacterial Effects on Drug-Resistant Escherichia coli Escape Variants

ACS Chemical Biology
Bharath SrinivasanJeffrey Skolnick

Abstract

In drug discovery, systematic variations of substituents on a common scaffold and bioisosteric replacements are often used to generate diversity and obtain molecules with better biological effects. However, this could saturate the small-molecule diversity pool resulting in drug resistance. On the other hand, conventional drug discovery relies on targeting known pockets on protein surfaces leading to drug resistance by mutations of critical pocket residues. Here, we present a two-pronged strategy of designing novel drugs that target unique pockets on a protein's surface to overcome the above problems. Dihydrofolate reductase, DHFR, is a critical enzyme involved in thymidine and purine nucleotide biosynthesis. Several classes of compounds that are structural analogues of the substrate dihydrofolate have been explored for their antifolate activity. Here, we describe 10 novel small-molecule inhibitors of Escherichia coli DHFR, EcDHFR, belonging to the stilbenoid, deoxybenzoin, and chalcone family of compounds discovered by a combination of pocket-based virtual ligand screening and systematic scaffold hopping. These inhibitors show a unique uncompetitive or noncompetitive inhibition mechanism, distinct from those reported for all kn...Continue Reading

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Citations

Sep 16, 2017·Scientia pharmaceutica·Pimonluck SittikornpaiboonLuckhana Lawtrakul
Oct 31, 2019·Evidence-based Complementary and Alternative Medicine : ECAM·Franklyn Nonso IheagwamShalom Nwodo Chinedu
Aug 29, 2018·MedChemComm·Brooke A Andrews, R Brian Dyer
Mar 15, 2019·Structural Dynamics·Hongnan Cao, Jeffrey Skolnick

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