Molecular dynamics study-guided identification of cyclic amine structures as novel hydrophobic tail components of hPPARγ agonists

Yuta Tanaka, Kanae Gamo, Takuji Oyama, Masao Ohashi, Minoru Waki, Kenji Matsuno, Nobuyasu Matsuura, Hiroaki Tokiwa, Hiroyuki Miyachi

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

We previously reported that a α-benzylphenylpropanoic acid-type hPPARγ-selective agonist with a piperidine ring as the hydrophobic tail part (3) exhibited sub-micromolar-order hPPARγ agonistic activity. In order to enhance the activity, we planned to carry out structural development based on information obtained from the X-ray crystal structure of hPPARγ ligand binding domain (LBD) complexed with 3. However, the shape and/or nature of the binding pocket surrounding the piperidine ring of 3 could not be precisely delineated because the structure of the omega loop of the LBD was poorly defined. Therefore, we constructed and inserted a plausible omega loop by means of molecular dynamics simulation. We then used the reconstructed LBD structure to design new mono-, bi- and tricyclic amine-bearing compounds that might be expected to show greater binding affinity for the LBD. Here, we describe synthesis and evaluation of α-benzylphenylpropanoic acid derivatives 8. As expected, most of the newly synthesized compounds exhibited more potent hPPARγ agonistic activity and greater hPPARγ binding affinity than 3. Some of these compounds also showed comparable aqueous solubility to 3.

Original languageEnglish
Pages (from-to)4001-4005
Number of pages5
JournalBioorganic and Medicinal Chemistry Letters
Volume24
Issue number16
DOIs
Publication statusPublished - Aug 15 2014

Fingerprint

Molecular Dynamics Simulation
Amines
Molecular dynamics
Ligands
Bearings (structural)
Acids
Solubility
Crystal structure
X-Rays
Derivatives
X rays
Computer simulation
piperidine

Keywords

  • Cyclic amine
  • Molecular dynamics simulation
  • Peroxisome proliferator-activated receptor gamma

ASJC Scopus subject areas

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

Cite this

Molecular dynamics study-guided identification of cyclic amine structures as novel hydrophobic tail components of hPPARγ agonists. / Tanaka, Yuta; Gamo, Kanae; Oyama, Takuji; Ohashi, Masao; Waki, Minoru; Matsuno, Kenji; Matsuura, Nobuyasu; Tokiwa, Hiroaki; Miyachi, Hiroyuki.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 24, No. 16, 15.08.2014, p. 4001-4005.

Research output: Contribution to journalArticle

Tanaka, Yuta ; Gamo, Kanae ; Oyama, Takuji ; Ohashi, Masao ; Waki, Minoru ; Matsuno, Kenji ; Matsuura, Nobuyasu ; Tokiwa, Hiroaki ; Miyachi, Hiroyuki. / Molecular dynamics study-guided identification of cyclic amine structures as novel hydrophobic tail components of hPPARγ agonists. In: Bioorganic and Medicinal Chemistry Letters. 2014 ; Vol. 24, No. 16. pp. 4001-4005.
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