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

Research output: Contribution to journalArticle

13 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1882-1897
Number of pages16
JournalApplied Biochemistry and Biotechnology
Volume172
Issue number4
DOIs
Publication statusPublished - 2014 Feb

All Science Journal Classification (ASJC) codes

  • Biotechnology
  • Bioengineering
  • Biochemistry
  • Applied Microbiology and Biotechnology
  • Molecular Biology

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