CPSA Digest 2002

Proceedings -Wednesday, October 9, 2002

WeOC9

Structural Awareness Spanning All Aspects of Instrumental Analysis in Pharmaceutical R&D

Background
Current advances in biology have been influenced by sequencing of the human genome. However, knowledge of DNA structure is only the beginning to understanding protein chemistry. The task of protein sequencing has now become an experiment in protein identification. Once sample preparation is completed, a protein can be identified in under an hour if its sequence is previously contained within a database. This improvement in the speed with which proteins can be identified is due in large part to advances in mass spectrometry (MS). Using MS, low femtomole amounts of peptides produced from enzymatic digestion of SDS-PAGE derived bands are sufficient to identify proteins from a database. Using this facility in combination with gene tagging techniques and one- or two-step affinity purification protocols makes it possible to identify the composition of protein complexes and identify enzyme substrates. This presentation discusses how various signaling pathways have become unraveled, or determined, using mass spectrometry techniques.

ACD/Labs designs user-friendly computational tools that use a structure-based approach to interpret spectra and chromatograms, and to generate systematic names and physical chemical properties. The software supports major vendor formats and unites important pharmaceutical analytical techniques, encompassing many diverse data types and structural identities. Libraries and query tools facilitate retrieval of knowledge based on chemical considerations. This proven software toolkit addresses pharmaceutical demands for efficiency by facilitating structure to analytical data integration.

According to an old Indian fable called the "six blind men and the elephant," partial knowledge can lead to controversy if handled improperly. In the story, a heated argument resulted when the blind men were asked to describe an elephant because each had a different description according to the part of the elephant they had encountered. The noise from the argument awoke the king, whom after listening to each man's story combined each factual version into a complementary and non-contradictory form describing the elephant. Analytical chemists experience analytes through the narrow bias of their particular analytical technique and often the correct overall interpretation of the substance can only be achieved by combining results from different types of experiments in a coherent fashion.

ACD/Labs computer software plays the role of the king in this old fable because it excels at combining analytical knowledge provided by different types of experiments. It lets you manage and view various analytical data types in parallel. Further, it lets you link the different pieces to multiple structures deduced from the acquired knowledge. The result is a complete and detailed solution to the question being asked. The Figure below shows how the proposed structure for a buspirone metabolite evolves in ACD/Labs software as new knowledge is acquired. Initially, we start with 11 possible unique hydroxyl buspirone metabolites, which are narrowed to two using the ACD/Labs auto assignment of the mass spectrum, and on to the final characterization through NMR. In brief, by using ACD/Labs software in combination with analytical data, the location of the hydroxyl group can be narrowed down to a few specific locations in a powerful and intuitive way. This approach defines the phrase, "structure awareness with respect to analytical techniques." The greater clarity afforded by this approach can remove several days' time from a week's analysis.

The structure of hydroxy buspirone and all the possible locations of the hydroxyl group (shaded region) as more data becomes available.

Company website: www.acdlabs.com

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