title: Identification of novel rab27a/melanophilin blockers by pharmacophore-based virtual screening.
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.
authors.affiliation: Bioinformatics and Molecular Design Research Center, Seoul, 120-749, Republic of Korea.
authors.forename: Jong Young
authors.initials: JY
authors.lastname: Joung
authors.forename: Ha Yeon
authors.initials: HY
authors.lastname: Lee
authors.forename: Jongil
authors.initials: J
authors.lastname: Park
authors.forename: Jee-Young
authors.initials: JY
authors.lastname: Lee
authors.forename: Byung Ha
authors.initials: BH
authors.lastname: Chang
authors.forename: Kyoung Tai
authors.initials: KT
authors.lastname: No
authors.forename: Ky-Youb
authors.initials: KY
authors.lastname: Nam
authors.forename: Jae Sung
authors.initials: JS
authors.lastname: Hwang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry*; D000818:Animals; D006801:Humans; D008544:Melanocytes / Q000378:metabolism; D020460:Melanosomes / Q000737:chemistry*; D013329:Structure-Activity Relationship; D020691:rab GTP-Binding Proteins / Q000737:chemistry*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D020691:rab GTP-Binding Proteins