Identification of Novel Rab27a/Melanophilin Blockers by Pharmacophore-Based Virtual Screening
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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.
KeywordsRab27a/melanophilin Pharmacophore-based virtual screening Skin pigmentation Mekanosome tansport Molecular docking
- 10.Wilson, S. M., Yip, R., Swing, D. A., O'Sullivan, T. N., Zhang, Y., Novak, E. K., Swank, R. T., Russell, L. B., Copeland, N. G., & Jenkins, N. A. (2000). A mutation in Rab27a causes the vesicle transport defects observed in ashen mice. Proceedings of the National Academy of Sciences of the United States of America, 97, 7933–7938.CrossRefGoogle Scholar
- 16.Barillari, C., Marcou, G., & Rognan, D. (2008). Hot-spots-guided receptor-based pharmacophores (HS-pharm): a knowledge-based approach to identify ligand-anchoring atoms in protein cavities and prioritize structure-based pharmacophores. Journal of Chemical Information and Modeling, 48, 1396–1410.CrossRefGoogle Scholar
- 17.(2010) Discovery Studio 3.0., Accelrys Inc., San Diego, CA. U.S.A.Google Scholar
- 18.(2005) Catalyst 4.10. Accelrys Inc, San Diego, CA, USA.Google Scholar
- 27.Allen, J. G., Bourbeau, M. P., Wohlhieter, G. E., Bartberger, M. D., Michelsen, K., Hungate, R., Gadwood, R. C., Gaston, R. D., Evans, B., Mann, L. W., Matison, M. E., Schneider, S., Huang, X., Yu, D., Andrews, P. S., Reichelt, A., Long, A. M., Yakowec, P., Yang, E. Y., Lee, T. A., & Oliner, J. D. (2009). Discovery and optimization of chromenotriazolopyrimidines as potent inhibitors of the mouse double minute 2-tumor protein 53 protein–protein interaction. Journal of Medicinal Chemistry, 52, 7044–7053.CrossRefGoogle Scholar
- 32.Hardcastle, I. R., Liu, J., Valeur, E., Watson, A., Ahmed, S. U., Blackburn, T. J., Bennaceur, K., Clegg, W., Drummond, C., Endicott, J. A., Golding, B. T., Griffin, R. J., Gruber, J., Haggerty, K., Harrington, R. W., Hutton, C., Kemp, S., Lu, X., McDonnell, J. M., Newell, D. R., Noble, M. E. M., Payne, S. L., Revill, C. H., Riedinger, C., Xu, Q., & Lunec, J. (2011). Isoindolinone inhibitors of the murine double minute 2 (MDM2)-p53 protein–protein interaction: structure–activity studies leading to improved potency. Journal of Medicinal Chemistry, 54, 1233–1243.CrossRefGoogle Scholar
- 33.Merck. Study of MK-8242 alone and in combination with cytarabine in participants with acute myelogenous leukemia (http://clinicaltrials.gov/show/NCT01451437)
- 34.Rew, Y., Sun, D., Gonzalez-Lopez De Turiso, F., Bartberger, M. D., Beck, H. P., Canon, J., Chen, A., Chow, D., Deignan, J., Fox, B. M., Gustin, D., Huang, X., Jiang, M., Jiao, X., Jin, L., Kayser, F., Kopecky, D. J., Li, Y., Lo, M. C., Long, A. M., Michelsen, K., Oliner, J. D., Osgood, T., Ragains, M., Saiki, A. Y., Schneider, S., Toteva, M., Yakowec, P., Yan, X., Ye, Q., Yu, D., Zhao, X., Zhou, J., Medina, J. C., & Olson, S. H. (2012). Structure-based design of novel inhibitors of the MDM2–p53 interaction. Journal of Medicinal Chemistry, 55, 4936–4954.CrossRefGoogle Scholar
- 35.A study of RO5045337 [RG7112] in patients with advanced solid tumors. Available from: http://www.clinicaltrials.gov/ct2/show/NCT00559533?term=RG7112&rank=1.