Abstract
To combine the potency of trimetrexate (TMQ) or piritrexim (PTX) with the species selectivity of trimethoprim (TMP), target based design was carried out with the X-ray crystal structure of human dihydrofolate reductase (hDHFR) and the homology model of Pneumocystis jirovecii DHFR (pjDHFR). Using variation of amino acids such as Met33/Phe31 (in pjDHFR/hDHFR) that affect the binding of inhibitors due to their distinct positive or negative steric effect at the active binding site of the inhibitor, we designed a series of substituted-pyrrolo[2,3-d]pyrimidines. The best analogs displayed better potency (IC50) than PTX and high selectivity for pjDHFR versus hDHFR, with 4 exhibiting a selectivity for pjDHFR of 24-fold.
Keywords:
DHFR inhibitors; Opportunistic infections; Pneumocystis pneumonia; Pyrrolo[2,3-d]pyrimidines; hDHFR; pjDHFR.
Copyright © 2018 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Amino Acids / chemistry*
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Anti-Bacterial Agents / chemical synthesis
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Anti-Bacterial Agents / pharmacology*
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Catalytic Domain
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Crystallography, X-Ray
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Drug Design
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Enzyme Assays
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Folic Acid Antagonists / chemical synthesis
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Folic Acid Antagonists / chemistry
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Folic Acid Antagonists / metabolism
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Folic Acid Antagonists / pharmacology*
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Humans
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Hydrogen Bonding
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Hydrophobic and Hydrophilic Interactions
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Molecular Docking Simulation
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Molecular Structure
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Pneumocystis carinii / enzymology
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Protein Binding
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Pyrimidines / chemical synthesis
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Pyrimidines / chemistry
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Pyrimidines / metabolism
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Pyrimidines / pharmacology*
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Pyrroles / chemical synthesis
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Pyrroles / chemistry
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Pyrroles / metabolism
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Pyrroles / pharmacology*
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Sequence Homology, Amino Acid
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Species Specificity
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Tetrahydrofolate Dehydrogenase / chemistry
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Tetrahydrofolate Dehydrogenase / metabolism
Substances
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Amino Acids
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Anti-Bacterial Agents
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Folic Acid Antagonists
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Pyrimidines
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Pyrroles
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Tetrahydrofolate Dehydrogenase