Personal Foreword

Mass spectrometry has been a well established technique in analytical chemistry for more than five decades, but its use to characterize target-ligand interactions is comparatively new. Only the availability of modern mass spectrometers achieving sufficient accuracy and sensitivity as well as the advent of soft ionization techniques such as ESI or MALDI has paved the way for successful studies in this field. From the first investigations in the early 1990s until now a great variety of mass spectrometry-based approaches covering target-ligand interactions have been implemented in the drug discovery process, so that drug-ligand interactions can be explored from almost every perspective: it is possible to focus on the li-gand, the target-ligand complex or the target (i.e. its binding site). Among the numerous advantages that qualify mass spectrometry for this purpose are two that should be emphasized: First, mass spectrometry offers the possibility to monitor the interacting partners without labelling either the ligand or the target. Second, mass spectrometry has the capability to identify structurally unknown hits, i.e. compounds binding to the target, from huge combinatorial compound libraries. Conversely, mass spectrometry can also provide an insight into the molecular structure of the binding domains on macromolecular targets.

It is the intention of this book to give an overview of the opportunities that mass spectrometry provides in medicinal chemistry, focusing primarily on the early drug discovery process. Therefore, particular emphasis is put on screening procedures for low relative molecular mass drug candidates supplemented by other approaches suitable to elucidate target-ligand interactions and the field of pharmacokinetic investigations. Instead of giving a complete summary of this topic, which would be clearly beyond the scope of a single book, selected approaches are presented reflecting the diversity of possible strategies.

For those readers who are not yet familiar with mass spectrometry, the introduction provides an explanation of the basics of mass spectrometry and its instrumentation as well as practical aspects and applications in bioanalysis. Next, a block of three chapters shows different affinity selection procedures suitable to identify hits from combinatorial compound libraries. This subject, being metaphorically speaking a search for a needle in a haystack, is of outstanding relevance for ''big pharma''. The techniques described here offer real high throughput capabilities and are implemented already in the routine industrial screening process. The next three chapters present more techniques also dealing with small molecule screening. One approach combines the biological assay directly with the analytical method using microcoil reactors integrated in a HPLC system to study target--ligand interactions. Another is based on the unique features of frontal affinity chromatography and has already proved its potential in several screening projects. The last one is a very simple but also very effective approach that enables binding assays with native, i.e. nonlabelled markers in analogy to conventional radioligand binding assays. Although ESI clearly dominates mass spectrometric screening procedures, MALDI and other ionization techniques based on laser desorption can also be utilized for this purpose. This is documented in the following chapter summing up recent advances in this field. In a further chapter the challenging concept of fragment-based drug discovery is presented which makes use of dynamic equilibrium processes in order to accumulate fragments with rather moderate affinity to a target binding site by forming a covalent bond to a linker. Even though this concept is basically a synthetic approach, its success is unambiguously connected to the use of mass spectrometry. The topic of target-ligand interactions presented in the preceding chapters is rounded off by two chapters showing mass spectrometric strategies benefiting from hydrogen deuterium exchange at the target. In one approach the deuterium uptake by the target as a function of the test compound is quantified in order to deduce binding affinity or stoichiometry. The other approach describes the possibility to characterize protein structure and conformational changes of proteins as well as how to localize the physical interactions between target and ligand, based on the exact assignment of target incorporated deuterium atoms in proteolytically generated peptide fragments. The last chapter touches on the issue of pharmacokinetics where mass spectrometry traditionally plays a prominent role. The fact that these mass spectrometric investigations can help to avoid failures in later clinical trials further illustrates the immense value of mass spectrometry for the drug discovery process.

As editors we would also like to take the opportunity to cordially thank all authors for their contributions. We hope that the applications collected in this book will give the reader an idea of the capabilities of mass spectrometry when used in the early stages of drug discovery. Considering that mass spectrometry only began to have an impact on early drug discovery in the past decade, we can expect that this process will be further accelerated in the near future by the rapidly proceeding evolution of mass spectrometry as an analytical tool to screen bioactivity.

Munich, November 2006 Klaus T. Wanner Georg Hofner

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