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.
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Authors | Khushbu Shah, Xin Lin, Sherry F Queener, Vivian Cody, Jim Pace, Aleem Gangjee |
Journal | Bioorganic & medicinal chemistry
(Bioorg Med Chem)
Vol. 26
Issue 9
Pg. 2640-2650
(05 15 2018)
ISSN: 1464-3391 [Electronic] England |
PMID | 29691153
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
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Copyright | Copyright © 2018 Elsevier Ltd. All rights reserved. |
Chemical References |
- Amino Acids
- Anti-Bacterial Agents
- Folic Acid Antagonists
- Pyrimidines
- Pyrroles
- Tetrahydrofolate Dehydrogenase
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Topics |
- Amino Acids
(chemistry)
- Anti-Bacterial Agents
(chemical synthesis, pharmacology)
- Catalytic Domain
- Crystallography, X-Ray
- Drug Design
- Enzyme Assays
- Folic Acid Antagonists
(chemical synthesis, chemistry, metabolism, pharmacology)
- Humans
- Hydrogen Bonding
- Hydrophobic and Hydrophilic Interactions
- Molecular Docking Simulation
- Molecular Structure
- Pneumocystis carinii
(enzymology)
- Protein Binding
- Pyrimidines
(chemical synthesis, chemistry, metabolism, pharmacology)
- Pyrroles
(chemical synthesis, chemistry, metabolism, pharmacology)
- Sequence Homology, Amino Acid
- Species Specificity
- Tetrahydrofolate Dehydrogenase
(chemistry, metabolism)
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