title: Computational structure-activity study directs synthesis of novel antitumor enkephalin analogs.
abstract: The capability of a Support Vector Machines QSAR model to predict the antiproliferative ability of small peptides was evaluated by screening a virtual library of enkephalin-like analogs modified by incorporation of the (R,S)-(1-adamantyl)glycine (Aaa) residue. From an initial set of 390 compounds, the peptides, Tyr-Aaa-Gly-Phe-Met (2), Tyr-Aaa-Gly-Phe-Phe (3), Phe-Aaa-Gly-Phe-Phe (4) and Phe-Aaa-Gly-Phe-Met (5) were selected, synthesized and their antitumor activity was tested and compared to that of Met-enkephalin (1). The antiproliferative activity correlated with the computational prediction and with the foldamer-forming ability of the studied peptides. The most active compounds were the hydrophobic peptides, Phe-Aaa-Gly-Phe-Phe (4) and Phe-Aaa-Gly-Phe-Met (5), having a greater propensity to adopt folded structures than the other peptides.
authors.affiliation: Division of Organic Chemistry and Biochemistry, Ruder Bosković Institute, Bijenicka c. 54, POB 180, Zagreb, 10002, Croatia.
authors.forename: M
authors.initials: M
authors.lastname: Gredicak
authors.forename: F
authors.initials: F
authors.lastname: Supek
authors.forename: M
authors.initials: M
authors.lastname: Kralj
authors.forename: Z
authors.initials: Z
authors.lastname: Majer
authors.forename: M
authors.initials: M
authors.lastname: Hollósi
authors.forename: T
authors.initials: T
authors.lastname: Smuc
authors.forename: K
authors.initials: K
authors.lastname: Mlinarić-Majerski
authors.forename: S
authors.initials: S
authors.lastname: Horvat
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives / Q000737:chemistry; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001185:Artificial Intelligence; D045744:Cell Line, Tumor; D002942:Circular Dichroism; D019295:Computational Biology / Q000379:methods*; D054697:Cytostatic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016208:Databases, Factual; D015195:Drug Design; D004744:Enkephalin, Methionine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008958:Models, Molecular; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D025341:Principal Component Analysis; D011487:Protein Conformation; D021281:Quantitative Structure-Activity Relationship; D012984:Software
chemical_list: D000970:Antineoplastic Agents; D054697:Cytostatic Agents; D009842:Oligopeptides; C551073:phenylalanyl-1-adamantylacetic acid-glycyl-phenylalanyl-methionine; C551074:phenylalanyl-1-adamantylacetic acid-glycyl-phenylalanyl-phenylalanine; D004744:Enkephalin, Methionine; D000218:Adamantane