Evolutionary combinatorial chemistry, a novel tool for SAR studies on peptide transport across the blood-brain barrier. Part 2. Design, synthesis and evaluation of a first generation of peptides.
The use of high-throughput methods in drug discovery allows the generation and testing of a large number of compounds, but at the price of providing redundant information. Evolutionary combinatorial chemistry combines the selection and synthesis of biologically active compounds with artificial intelligence optimization methods, such as genetic algorithms (GA). Drug candidates for the treatment of central nervous system (CNS) disorders must overcome the blood-brain barrier (BBB). This paper reports a new genetic algorithm that searches for the optimal physicochemical properties for peptide transport across the blood-brain barrier. A first generation of peptides has been generated and synthesized. Due to the high content of N-methyl amino acids present in most of these peptides, their syntheses were especially challenging due to over-incorporations, deletions and DKP formations. Distinct fragmentation patterns during peptide cleavage have been identified. The first generation of peptides has been studied by evaluation techniques such as immobilized artificial membrane chromatography (IAMC), a cell-based assay, log Poctanol/water calculations, etc. Finally, a second generation has been proposed.
Teixidó
Meritxell
M
Institut de Recerca Biomèdica de Barcelona (IRBB-PCB), Parc Científic de Barcelona, Josep Samitier, 1-5. E-08028, Barcelona, Spain.
Belda
Ignasi
I
Zurita
Esther
E
Llorà
Xavier
X
Fabre
Myriam
M
Vilaró
Senén
S
Albericio
Fernando
F
Giralt
Ernest
E
D000465:Algorithms; D000818:Animals; D001185:Artificial Intelligence; D001692:Biological Transport; D001812:Blood-Brain Barrier / Q000378:metabolism; D002417:Cattle; D002478:Cells, Cultured; D020650:Combinatorial Chemistry Techniques; D019151:Peptide Library; D010455:Peptides / Q000138:chemical synthesis* / Q000378:metabolism / Q000627:therapeutic use; D004364:Pharmaceutical Preparations / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D051381:Rats; D013329:Structure-Activity Relationship
D019151:Peptide Library; D010455:Peptides; D004364:Pharmaceutical Preparations