Structure–Activity Relationships by NMR: A New Procedure for Drug Discovery by a Combinatorial–Rational Approach
✍ Scribed by Prof. Dr. Horst Kessler
- Publisher
- John Wiley and Sons
- Year
- 1997
- Tongue
- English
- Weight
- 422 KB
- Volume
- 36
- Category
- Article
- ISSN
- 0044-8249
No coin nor oath required. For personal study only.
✦ Synopsis
The search for new lead structures for drug development was always a combination of serendipity and rational design. The possibility of discovering new, biologically active structures was dramatically increased by screening pools of substances. In the rational approach medicinal chemists optimized the properties of the active compound either using personal experience only or partly utilizing molecular structure. Disillusionment followed the extreme overemphasis of rational design (which certainly was stimulated by the suggestive power of colored computer pictures of the molecules), because it was soon evident that a medicinal product with desired and distinct properties such as high activity and selectivity, metabolic stability, and bioavailability cannot be attained simply by molecular design. However. directly or indirectly, design certainly plays a significant role in developing new pharmaceutical products.
Recently eminent representatives of the pharmaceutical research field have expressed the opinion that rational design does not work. Instead they concentrate fully on the combinatorial approach. Combi-chem. the new buzzword, will certainly give new impetus to pharmaceutical research['] but again disillusionment will soon follow, as limitations are already obvious in this new development.1'1 Extreme viewpoints always have a short lifespan, and the choice will not be between combi-chem or rational design, but a combination of the techniques will be used to accelerate the development of new drugs.
In recent years our understanding of biological processes in healthy or afflicted organisms has brought the identification of ever increasing numbers of molecular structures, whose inhibiting or activating factors reveal a promising goal for phannaceutical products. In this regard proteins in the form of enzymes, receptors, or inhibitors play a decisive role. Their biotechnological identification, expression, isotope labeling, and structural clarification allows a targeted, structure-oriented search for partners that build supramolecular complexes with the desired biologicril effect.
Development of substrates with optimal adaption to clefts and pockets of protein receptors is more complicated than expected. Molecular recognition is not a simple docking of given surfaces but is based on a double-induced fit. in which both [