ArticleBiochemistry2013
Elucidating features that drive the design of selective antifolates using crystal structures of human dihydrofolate reductase.
Article in Biochemistry, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 40 citations in OpenAlex.
- Chlordiazepoxide against signalling, receptor and regulatory proteins of breast cancer: a structure-based in-silico approach.Medical oncology (Northwood, London, England) · 2024Article
- Novel tetrahydroisoquinolines as DHFR and CDK2 inhibitors: synthesis, characterization, anticancer activity and antioxidant properties.BMC chemistry · 2024Article
- Structure-Based In Silico Approaches Reveal IRESSA as a Multitargeted Breast Cancer Regulatory, Signalling, and Receptor Protein Inhibitor.Pharmaceuticals (Basel, Switzerland) · 2024Article
- Drug Discovery Efforts to Identify Novel Treatments for Neglected Tropical Diseases - Cysteine Protease Inhibitors.Current medicinal chemistry · 2024Review
- A novel antifolate suppresses growth of FPGS-deficient cells and overcomes methotrexate resistance.Life science alliance · 2023Article
- Promising Antifungal Molecules against Mucormycosis Agents Identified from Pandemic Response BoxJournal of fungi (Basel, Switzerland) · 2023Article
- Structure-guided functional studies of plasmid-encoded dihydrofolate reductases reveal a common mechanism of trimethoprim resistance in Gram-negative pathogens.Communications biology · 2022Article
- The Complementarity Principle-One More Step towards Analytical Docking on the Example of Dihydrofolate Reductase Complexes.Life (Basel, Switzerland) · 2021Article
- Synthesis, Biological Activity, and Molecular Dynamics Study of Novel Series of a Trimethoprim Analogs as Multi-Targeted Compounds: Dihydrofolate Reductase (DHFR) Inhibitors and DNA-Binding Agents.International journal of molecular sciences · 2021Article
- Multistage and transmission-blocking targeted antimalarials discovered from the open-source MMV Pandemic Response Box.Nature communications · 2021Article
- The Structural Basis for Nonsteroidal Anti-Inflammatory Drug Inhibition of Human Dihydrofolate Reductase.Journal of medicinal chemistry · 2020Article
- Drugging the Folate Pathway in Mycobacterium tuberculosis: The Role of Multi-targeting Agents.Cell chemical biology · 2019Article
- Discovery of Selective Toxoplasma gondii Dihydrofolate Reductase Inhibitors for the Treatment of Toxoplasmosis.Journal of medicinal chemistry · 2019Article
- Expression, purification, and inhibition profile of dihydrofolate reductase from the filarial nematode Wuchereria bancrofti.PloS one · 2018Article
- Direct Substitution of Arylalkynyl Carbinols Provides Access to Diverse Terminal Acetylene Building Blocks.Organic letters · 2017Article
- Structural diversity in the host-guest complexes of the antifolate pemetrexed with native cyclodextrins: gas phase, solution and solid state studies.Beilstein journal of organic chemistry · 2017Article
- Discovery of Potent and Selective Leads againstACS medicinal chemistry letters · 2016Article
- Ligand-Dependent Conformational Dynamics of Dihydrofolate Reductase.Biochemistry · 2016Article
- Endless Resistance. Endless Antibiotics?MedChemComm · 2016Article
- Propargyl-Linked Antifolates Are Potent Inhibitors of Drug-Sensitive and Drug-Resistant Mycobacterium tuberculosis.PloS one · 2016Article
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
The pursuit of antimicrobial drugs that target dihydrofolate reductase (DHFR) exploits differences in sequence and dynamics between the pathogenic and human enzymes. Here, we present five crystal structures of human DHFR bound to a new class of antimicrobial agents, the propargyl-linked antifolates (PLAs), with a range of potency (IC50 values of 0.045-1.07 μM) for human DHFR. These structures reveal that interactions between the ligands and Asn 64, Phe 31, and Phe 34 are important for increased affinity for human DHFR and that loop residues 58-64 undergo ligand-induced conformational changes. The utility of these structural studies was demonstrated through the design of three new ligands that reduce the number of contacts with Asn 64, Phe 31, and Phe 34. Synthesis and evaluation show that one of the designed inhibitors exhibits the lowest affinity for human DHFR of any of the PLAs (2.64 μM). Comparisons of structures of human and Staphylococcus aureus DHFR bound to the same PLA reveal a conformational change in the ligand that enhances interactions with residues Phe 92 (Val 115 in huDHFR) and Ile 50 (Ile 60 in huDHFR) in S. aureus DHFR, yielding selectivity. Likewise, comparisons of human and Candida glabrata DHFR bound to the same ligand show that hydrophobic interactions with residues Ile 121 and Phe 66 (Val 115 and Asn 64 in human DHFR) yield selective inhibitors. The identification of residue substitutions that are important for selectivity and the observation of active site flexibility will help guide antimicrobial antifolate development for the inhibition of pathogenic species.
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Registered trials
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