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

Khushbu Shah, Xin Lin, Sherry Queener, Vivian Cody, Jim Pace, Aleem Gangjee

Research output: Contribution to journalArticle

1 Citation (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)2640-2650
Number of pages11
JournalBioorganic and Medicinal Chemistry
Volume26
Issue number9
DOIs
StatePublished - May 15 2018

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Folic Acid Antagonists
Pneumocystis carinii
Tetrahydrofolate Dehydrogenase
Opportunistic Infections
Amino Acids
Trimetrexate
Trimethoprim
Crystal structure
Binding Sites
Inhibitory Concentration 50
X rays
Catalytic Domain
X-Rays
Pyrrolo(2,3-d)pyrimidine
piritrexim

Keywords

  • DHFR inhibitors
  • hDHFR
  • Opportunistic infections
  • pjDHFR
  • Pneumocystis pneumonia
  • Pyrrolo[2,3-d]pyrimidines

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

Cite this

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title = "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.",
keywords = "DHFR inhibitors, hDHFR, Opportunistic infections, pjDHFR, Pneumocystis pneumonia, Pyrrolo[2,3-d]pyrimidines",
author = "Khushbu Shah and Xin Lin and Sherry Queener and Vivian Cody and Jim Pace and Aleem Gangjee",
year = "2018",
month = "5",
day = "15",
doi = "10.1016/j.bmc.2018.04.032",
language = "English (US)",
volume = "26",
pages = "2640--2650",
journal = "Bioorganic and Medicinal Chemistry",
issn = "0968-0896",
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T2 - Design, synthesis and biological evaluation of 6-substituted pyrrolo[2,3-d]pyrimidines as dihydrofolate reductase inhibitors and potential anti-opportunistic infection agents

AU - Shah, Khushbu

AU - Lin, Xin

AU - Queener, Sherry

AU - Cody, Vivian

AU - Pace, Jim

AU - Gangjee, Aleem

PY - 2018/5/15

Y1 - 2018/5/15

N2 - 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.

AB - 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.

KW - DHFR inhibitors

KW - hDHFR

KW - Opportunistic infections

KW - pjDHFR

KW - Pneumocystis pneumonia

KW - Pyrrolo[2,3-d]pyrimidines

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