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Computational development of inhibitors of plasmid-borne bacterial dihydrofolate reductase
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Authors
Advisor(s)
Abstract(s)
Resistance to trimethoprim and other antibiotics targeting dihydrofolate reductase may
arise in bacteria harboring an atypical, plasmid-encoded, homotetrameric dihydrofolate reductase,
called R67 DHFR. Although developing inhibitors to this enzyme may be expected to be promising
drugs to fight trimethoprim-resistant strains, there is a paucity of reports describing the
development of such molecules. In this manuscript, we describe the design of promising lead
compounds to target R67 DHFR. Density-functional calculations were first used to identify the
modifications of the pterin core that yielded derivatives likely to bind the enzyme and not
susceptible to being acted upon by it. These unreactive molecules were then docked to the active
site, and the stability of the docking poses of the best candidates was analyzed through triplicate
molecular dynamics simulations, and compared to the binding stability of the enzyme–substrate
complex. Molecule 32 ([6-(methoxymethyl)-4-oxo-3,7-dihydro-4H-pyrano[2,3-d]pyrimidin-2-
yl]methyl-guanidinium) was shown by this methodology to afford extremely stable binding
towards R67 DHFR and to prevent simultaneous binding to the substrate. Additional docking and
molecular dynamics simulations further showed that this candidate also binds strongly to the
canonical prokaryotic dihydrofolate reductase and to human DHFR, and is therefore likely to be
useful to the development of chemotherapeutic agents and of dual-acting antibiotics that target the
two types of bacterial dihydrofolate reductase.
Description
Keywords
Computer-aided molecular design Molecular dynamics Density-functional theory Molecular docking Drug development
Citation
Silva P.J. Computational Development of Inhibitors of Plasmid-Borne Bacterial Dihydrofolate Reductase. Antibiotics. 2022; 11(6):779. https://doi.org/10.3390/antibiotics11060779
Publisher
MDPI