Development of a pharmacophore model for the catecholamine release-inhibitory peptide catestatin: Virtual screening and functional testing identify novel small molecule therapeutics of hypertension |
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| Authors: | Igor F. Tsigelny Valentina L. Kouznetsova Nilima Biswas Sushil K. Mahata Daniel T. O’Connor |
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| Affiliation: | 1. Department of Neurosciences, University of California at San Diego, La Jolla, CA 92093, United States;2. San Diego Supercomputer Center, University of California at San Diego, La Jolla, CA 92093, United States;3. Moores Cancer Center, University of California at San Diego, La Jolla, CA 92093, United States;4. Department of Medicine, University of California at San Diego, La Jolla, CA 92093, United States;5. Department of Pharmacology, University of California at San Diego, La Jolla, CA 92093, United States;6. Veterans Affairs San Diego Healthcare System, San Diego, CA 92161, United States |
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| Abstract: | The endogenous catecholamine release-inhibitory peptide catestatin (CST) regulates events leading to hypertension and cardiovascular disease. Earlier we studied the structure of CST by NMR, molecular modeling, and amino acid scanning mutagenesis. That structure has now been exploited for elucidation of interface pharmacophores that mediate binding of CST to its target, with consequent secretory inhibition. Designed pharmacophore models allowed screening of 3D structural domains. Selected compounds were tested on both cultured catecholaminergic cells and an in vivo model of hypertension; in each case, the candidates showed substantial mimicry of native CST actions, with preserved or enhanced potency and specificity. The approach and compounds have thus enabled rational design of novel drug candidates for treatment of hypertension or autonomic dysfunction. |
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| Keywords: | Catestatin Hypertension Pharmacophore Pharmacophore annotation Molecular database screening Molecular database search Molecular fingerprint Similarity clustering |
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