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.
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This study was supported by a grant of the Korea Healthcare technology R&D project, Ministry of Health & Welfare, Republic of Korea (grant no. A103017).
Jong Young Joung performed virtual screening, analyzed data, and wrote the paper; Ha Yeon Lee performed biological assays for hit compounds and wrote the paper; Jongil Park performed biological assays; Jee-Young Lee analyzed assay results; Byung Ha Chang analyzed SAR results; Kyoung Tai No designed experiments; Ky-Youb Nam designed experiments and wrote the paper; and Jae Sung Hwang designed the biological assays.
J. Y. Joung and H. Y. Lee contributed equally to this work.
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Joung, J.Y., Lee, H.Y., Park, J. et al. Identification of Novel Rab27a/Melanophilin Blockers by Pharmacophore-Based Virtual Screening. Appl Biochem Biotechnol 172, 1882–1897 (2014). https://doi.org/10.1007/s12010-013-0615-2
- Pharmacophore-based virtual screening
- Skin pigmentation
- Mekanosome tansport
- Molecular docking