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Article

Computational Development of Inhibitors of Plasmid-Borne Bacterial Dihydrofolate Reductase

1
FP-I3ID, FP-BHS, Faculdade de Ciências da Saúde, Universidade Fernando Pessoa, 4200-150 Porto, Portugal
2
[email protected], BioSIM, Departamento de Biomedicina, Faculdade de Medicina, Universidade do Porto, 4200-319 Porto, Portugal
Academic Editor: Martina Hrast
Antibiotics 2022, 11(6), 779; https://doi.org/10.3390/antibiotics11060779
Received: 18 May 2022 / Revised: 1 June 2022 / Accepted: 6 June 2022 / Published: 7 June 2022
(This article belongs to the Special Issue Design and Preparation of Antimicrobial Agents)
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. View Full-Text
Keywords: computer-aided molecular design; molecular dynamics; density-functional theory; molecular docking; drug development computer-aided molecular design; molecular dynamics; density-functional theory; molecular docking; drug development
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MDPI and ACS Style

Silva, P.J. Computational Development of Inhibitors of Plasmid-Borne Bacterial Dihydrofolate Reductase. Antibiotics 2022, 11, 779. https://doi.org/10.3390/antibiotics11060779

AMA Style

Silva PJ. Computational Development of Inhibitors of Plasmid-Borne Bacterial Dihydrofolate Reductase. Antibiotics. 2022; 11(6):779. https://doi.org/10.3390/antibiotics11060779

Chicago/Turabian Style

Silva, Pedro J. 2022. "Computational Development of Inhibitors of Plasmid-Borne Bacterial Dihydrofolate Reductase" Antibiotics 11, no. 6: 779. https://doi.org/10.3390/antibiotics11060779

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