HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

Targeting species specific amino acid residues: Design, synthesis and biological evaluation of 6-substituted pyrrolo[2,3-d]pyrimidines as dihydrofolate reductase inhibitors and potential anti-opportunistic infection agents.

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.
AuthorsKhushbu Shah, Xin Lin, Sherry F Queener, Vivian Cody, Jim Pace, Aleem Gangjee
JournalBioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 26 Issue 9 Pg. 2640-2650 (05 15 2018) ISSN: 1464-3391 [Electronic] England
PMID29691153 (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.)
CopyrightCopyright © 2018 Elsevier Ltd. All rights reserved.
Chemical References
  • Amino Acids
  • Anti-Bacterial Agents
  • Folic Acid Antagonists
  • Pyrimidines
  • Pyrroles
  • Tetrahydrofolate Dehydrogenase
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)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: