Design of Cyclic Peptides - Peptide and Protein Design for Biopharmaceutical Applications - page 131

4
Design of Cyclic Peptides
Oliver Demmer, Andreas O. Frank and Horst Kessler
4.1 INTRODUCTION
4.1.1 Pharmaceutical Research Today
Preclinical drug development has changed its paradigms several times
over the years. Since the focus shifted more and more toward rational
strategies, concepts for computational drug design were developed.
However, it became obvious that such approaches had great difficulties
due to mutual conformational adaptation in the docking process (flexible
keys and locks) and unpredictable water binding in the molecular inter-
phase [1]. Thus, in most cases, high-throughput screening (HTS) assays,
which are almost exclusively focused on small organic molecules, serve as
the available tool for discovering new drug molecules. Due to the high
number of 'false positives' and absent hits for several target receptors, the
limitations of HTS are obvious even when huge libraries are tested for
biological activity.
In conclusion, chemical biology has progressed to explore the 'chemi-
cal space', but it remains difficult to realize a substantial part of the
'biological space', i.e. to achieve sufficient but also directed diversity in
practice [2,3].
Due to the problems of HTS and common rational design approaches,
the interest of medicinal chemists turned back to peptides as potential
drug molecules. Although having a high biochemical potential (as