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 intel...

Full description

Saved in:
Bibliographic Details
Published in:Journal of peptide science 2005-12, Vol.11 (12), p.789-804
Main Authors: Teixidó, Meritxell, Belda, Ignasi, Zurita, Esther, Llorà, Xavier, Fabre, Myriam, Vilaró, Senén, Albericio, Fernando, Giralt, Ernest
Format: Article
Language:English
Subjects:
Algorithms
Animals
Artificial Intelligence
Biological Transport
blood-brain barrier
Blood-Brain Barrier - metabolism
Cattle
Cells, Cultured
Combinatorial Chemistry Techniques
genetic algorithm
N-methyl amino acids
Peptide Library
peptide transport
Peptides - chemical synthesis
Peptides - metabolism
Peptides - therapeutic use
Pharmaceutical Preparations - chemical synthesis
Pharmaceutical Preparations - chemistry
Pharmaceutical Preparations - metabolism
Rats
Structure-Activity Relationship
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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. Copyright © 2005 European Peptide Society and John Wiley & Sons, Ltd.
ISSN:1075-2617
1099-1387
DOI:10.1002/psc.679