Applied Biochemistry and Biotechnology

, Volume 172, Issue 4, pp 1882–1897

Identification of Novel Rab27a/Melanophilin Blockers by Pharmacophore-Based Virtual Screening

  • Jong Young Joung
  • Ha Yeon Lee
  • Jongil Park
  • Jee-Young Lee
  • Byung Ha Chang
  • Kyoung Tai No
  • Ky-Youb Nam
  • Jae Sung Hwang
Article

Abstract

Melanocytes are unique cells that produce specific melanin-containing intracellular organelles called melanosomes. Melanosomes are transported from the perinuclear area of melanocytes toward the plasma membrane as they become more melanized in order to increase skin pigmentation. In this vesicular trafficking of melanosomes, Rab27a, melanophilin, and myosin Va play crucial roles in linking melanosomes to actin-based motors. To identify novel compounds to inhibit binding interface between Rab27a and melanophilin, a pharmacophore model was built based on a modeled 3D structure of the protein complex that describes the essential binding residues in the intermolecular interaction. A pharmacophore model was employed to screen a chemical library database. Finally, 25 virtual hits were selected for biological evaluations. The biological activities of 11 analogues were evaluated in a second assay. Two compounds were identified as having concentration-dependent inhibitory activity. By analyzing structure–activity relationships of derivatives of BMD-20, two hydroxyl functional groups were found to be critical for blocking the intermolecular binding between Rab27a and melanophilin.

Keywords

Rab27a/melanophilin Pharmacophore-based virtual screening Skin pigmentation Mekanosome tansport Molecular docking 

Supplementary material

12010_2013_615_MOESM1_ESM.docx (8 kb)
Table S1(DOCX 7 kb)
12010_2013_615_MOESM2_ESM.docx (75 kb)
Figure S2(DOCX 75 kb)
12010_2013_615_MOESM3_ESM.docx (892 kb)
Figure S3(DOCX 892 kb)

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Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Jong Young Joung
    • 1
  • Ha Yeon Lee
    • 4
  • Jongil Park
    • 4
  • Jee-Young Lee
    • 1
  • Byung Ha Chang
    • 1
  • Kyoung Tai No
    • 3
  • Ky-Youb Nam
    • 1
    • 2
  • Jae Sung Hwang
    • 4
  1. 1.Bioinformatics and Molecular Design Research CenterSeoulRepublic of Korea
  2. 2.Gachon Institute of Pharmaceutical SciencesGachon UniversityIncheonRepublic of Korea
  3. 3.Department of Biotechnology and Translational Research Center for Protein Function ControlYonsei UniversitySeoulRepublic of Korea
  4. 4.Department of Genetic Engineering and Skin Biotechnology CenterKyung Hee UniversityYonginRepublic of Korea

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