title: Development of a pharmacophore model for the catecholamine release-inhibitory peptide catestatin: virtual screening and functional testing identify novel small molecule therapeutics of hypertension.
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.
authors.affiliation: Department of Neurosciences, University of California at San Diego, La Jolla, 92093, United States. itsigeln@ucsd.edu
authors.forename: Igor F
authors.initials: IF
authors.lastname: Tsigelny
authors.forename: Valentina L
authors.initials: VL
authors.lastname: Kouznetsova
authors.forename: Nilima
authors.initials: N
authors.lastname: Biswas
authors.forename: Sushil K
authors.initials: SK
authors.lastname: Mahata
authors.forename: Daniel T
authors.initials: DT
authors.lastname: O'Connor
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000959:Antihypertensive Agents / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D002118:Calcium / Q000378:metabolism; D002395:Catecholamines / Q000378:metabolism*; D053379:Chromogranin A / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D015195:Drug Design; D006339:Heart Rate / Q000187:drug effects; D006973:Hypertension / Q000188:drug therapy; D008958:Models, Molecular; D016716:PC12 Cells; D010446:Peptide Fragments / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats
chemical_list: D000959:Antihypertensive Agents; D002395:Catecholamines; D053379:Chromogranin A; D010446:Peptide Fragments; C109084:chromogranin A (344-364); D002118:Calcium
keywords: 3D; ASA; AchR; BP; CHGA; CST; Catestatin; DBP; DSI; Data Sciences International (St. Paul, MN); HR; Hypertension; Molecular database screening; Molecular database search; Molecular fingerprint; NMR; Pharmacophore; Pharmacophore annotation; SBP; SEM; Similarity clustering; acetylcholine receptor; blood pressure; catestatin; chromogranin A; diastolic blood pressure; heart rate; nuclear magnetic resonance; standard error of the mean; systolic blood pressure; three-dimensional; water-accessible surface area