Structure-based drug design identifies novel LPA3 antagonists

James I. Fells, Ryoko Tsukahara, Jianxiong Liu, Gabor Tigyi, Abby L. Parrill

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Compound 5 ([5-(3-nitrophenoxy)-1,3-dioxo-1,3-dihydro-2-isoindol-2-y1] acetic acid) was identified as a weak selective LPA3 antagonist (IC50 4504 nM) in a virtual screening effort to optimize a dual LPA2 and 3 antagonist. Structure-based drug design techniques were used to prioritize similarity search matches of compound 5. This strategy rapidly identified 10 novel antagonists. The two most efficacious compounds identified inhibit activation of the LPA3 receptor by 200 nM LPA with IC50 values of 752 nM and 299211M. These compounds additionally define changes to our previously reported pharmacophore that will improve its ability to identify more potent and selective LPA3 receptor antagonists. The results of the combined computational and experimental screening are reported.

Original languageEnglish (US)
Pages (from-to)7457-7464
Number of pages8
JournalBioorganic and Medicinal Chemistry
Volume17
Issue number21
DOIs
StatePublished - Nov 1 2009

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Lysophosphatidic Acid Receptors
Drug Design
Inhibitory Concentration 50
Screening
Acetic Acid
Pharmaceutical Preparations
Chemical activation

All Science Journal Classification (ASJC) codes

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

Cite this

Structure-based drug design identifies novel LPA3 antagonists. / Fells, James I.; Tsukahara, Ryoko; Liu, Jianxiong; Tigyi, Gabor; Parrill, Abby L.

In: Bioorganic and Medicinal Chemistry, Vol. 17, No. 21, 01.11.2009, p. 7457-7464.

Research output: Contribution to journalArticle

Fells, James I. ; Tsukahara, Ryoko ; Liu, Jianxiong ; Tigyi, Gabor ; Parrill, Abby L. / Structure-based drug design identifies novel LPA3 antagonists. In: Bioorganic and Medicinal Chemistry. 2009 ; Vol. 17, No. 21. pp. 7457-7464.
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