Automated molecular structure elucidation

For more than three decades now scientists have been striving for automatization of structure elucidation. The development of automated structure elucidation was accelerated by increasingly powerful computer hardware and software. In particular, chemical structures and their properties were digitalized and collected in databases. There are two fundamentally different methods of automated structure elucidation, 

This is, however, the most serious problem of database-based structure elucidation. Even the largest databases contain only tens of thousands or a few hundred thousand spectra to date. Thus, in the MS database NISTll [226], used in parts of the present work, there are 243,893 El-MS spectra belonging to 212,961 compounds. The database Beilstein used in Section 2.5 contains 8,711,107 known organic compounds, while the number of mathematically possible constitutions, even for a single molecular formula of low mass (about 150 Da), can exceed 100 million (see Appendix D). For example, the smallest (with respect to molecular mass) molecular formula associated with more than 100 million mathematically possible constitutions is Cg N2 0 (146 Da, 109,240,025 isomers). 

In the context of combinatorial chemistry, as well as in natural products chemistry, it is quite possible that the analyte of interest is not contained in spectrum databases. In recent years, the use of structural (or compound) databases for structure elucidation has increased due to the evolution of web-based services such as PubChem [218] and ChemSpider [259], with approximately 26 million entries each. These databases do not generally contain spectra (there are some exceptions) and as such only provide information about compounds that have been documented to exist. Although this is a smaller subset of possible structures for a given molecular formula than generating all mathematically possible structures, the same principles apply to determining the correct one as for generated structrues, without the guarantee that the correct struc- 

The idea of de novo structure elucidation is to find the correct structure without searching databases. A prominent starting point is the well known DENDRAL system [183], the development of which began already in the mid 1960 s. DENDRAL was developed for the automated structure elucidation of organic compounds by MS, after separation by gas chromatography (GC). 

DENDRAL is described in many computer science books as the first expert system. Moreover, it can be considered as one of the roots of chemoinformatics. Interestingly, even NASA was among the founders of this pioneering project, with the ambitious intention to supply future Mars missions with such software, to enable einalysis and interpretation of MS samples onboard a pilotless spacecraft and to broadcast only identified structural formulas back to earth instead of huge GC/MS data sets. 

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Biotechnology is one of the most influential sciences at the end of this century and the analytical control of biotechnological processes in laboratories and pilot and industrial plants Is therefore essential. Automation is a boon to the five analytical techniques most frequently employed In this field, namely electrophoresis, Immunoassay, chromatography, protein and DNA sequencing, and molecular structure elucidation. 

Expert systems have been extensively applied in many branches of analytical science, and in a number of noteworthy cases (generally involving molecular structure elucidation from spectroscopic data) such applications have led to the development of the technology. In addition to organic, molecular spectroscopy automated spectral interpretation systems have also been developed for X-ray diffraction. X-ray fluorescence, and, as advisors for instrument optimization, for atomic absorption spectrometry. 

M. Elyashberg, K. Blinov, and E. Martirosian. A new approach to computer-aided molecular structure elucidation The expert system Structure Elucidator. Lab. Autom. Inf Man., 34 15-30,1999. 

The following is a procedure recommended for elucidating the structure of complex organic molecules. It uses a combination of different NMR and other spectroscopic techniques. It assumes that the molecular formula has been deduced from elemental analysis or high-resolution mass spectrometry. Computer-based automated or interactive versions of similar approaches have also been devised for structural elucidation of complex natural products, such as SESAMI (systematic elucidation of structures by using artificial machine intelligence), but there is no substitute for the hard work, experience, and intuition of the chemist. 

The solid-bound library is treated with a labeled soluble biological target. For many studies a fluorescent label has been employed because of the high sensitivity of fluorescence detection. The labeled receptor binds to those resin beads that are derivatized with compounds that have the highest affinity to the biological receptor.The labeled beads are then selected followed by structural elucidation of the support-bound compound (see Section 1.4.1).The identity of the bioactive substance can be limited to a few alternative structures by mass spectrometric determination of the molecular mass. Highly efficient, automated methods have been developed to isolate the labeled beads, for example, by use of a fluorescence-activated cell sorting instrument [96]. 

High-throughput preparative HPLC coupled to electrospray ionization mass spectrometry (Chapter 17), which disposes upon a signal for collecting detected compounds of the defined molecular mass, is one of the highly promising new developments in this area. Such systems can be incorporated for synthesis purposes into the periphery of automated multicomponent systems, thus making a valuable contribution to the rationalization and quality enhancement of combinatorial synthesis processes. The combination of automated synthesis, purification and on-line instrumental identification (NMR, IR, MS) will become feasible in the near future, and as a matter of routine operation. Analytic methods of structure elucidation will then also be able to be combined with automated combinatorial chemistry. 

To meet the increasing demands on quality and efficiency of spectroscopic services a new approach to fully automated structure elucidation has been developed by the BASF company. Unlike other structure generators, such as the above-described Specinfo/Molgen combination, the BASF generator SpecSolv uses only C NMR spectra and does not require any further information from other spectroscopic techniques, not even knowledge of the molecular formula or element composition. 

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