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Studies of the molecular and electronic structures of small molecules for pharmacological and environmental applications


Objectives the aim of the present proposal is the determination of molecular structures at atomic resolution in order to gain in the understanding of systems of physicochemical, pharmacological and biological interest. In these studies, the scale of the problem is defined by so called small molecules in contrast to macromolecules, the most typical example of which are proteins. We shall be mainly interested in the study of three types of compounds, all of which require the same methodology for structure determination: 1)complexes of organic ligands with metals ions; 2)structure of molecules that are potential inhibitors of target enzymes in drug design; 3)molecular structure of natural products relevance we have chosen the three main lines of research above mentioned because they share several common features relevant to the present proposal. We have been working for several years in the determination of small-molecule structures, particularly in compounds which, like completes of chelating ligands with heavy metal atoms, are of extreme biological interest. Moreover, in the last few years, we have consolidated a research line in macromolecular crystallography which has by now produced several new protein structures, many of which are enzymes. The next step in the research procedure is to design and test small molecules which may behave as selective inhibitors of some of these enzymes. Also, our laboratory has considerable experience in the study of the molecular structure of natural compounds, particularly those of known biological activity. The analysis of these problems requires a three-dimensional characterization of the molecular structure, which is performed by the technique ofX-ray diffraction from a single-crystal of the sample.Methodology and executionTo be able to give the necessary support for these collaborative projects, it is absolutely necessary to provide our Laboratory with modern data collection and analysis facilites that would enable faster data collection in connection with the best possible data analysis software. For this reason, the main expenditure of the present Project will be the acquisition of a new X-ray single-crystal diffractometer with a modern CCD (Charge-Coupled Device) area detector. The project is planned to last four years. The activities involve synthesis, crystallization, structure determination and analysis. These steps are connected and very much dependent on one another and will be continuously executed throughout the duration of the project. Nevertheless, we are proposing a set of intermediate goals and a schedule for the project, to facilitate its follow up. Typically, we expect that, for every year we shall determine: four calixarene structures, ten structures of metal chelating molecules, five structures of natural products, five compounds with potential enzyme inhibitory activity. Also, three crystals per year will be studied to ultra-high resolution with fine electron density measurements. As a fundamental aspect, it is important to stress that the advantages of this new euipment are not merely related to speed, but, above all, to the quality and precision of the measurements to be performed. During the initial period of the project, when the equipment will not be available, several compounds will be synthesized and crystallized and several spectroscopic and thermodynamical studies will be carried out while the CCD diffractometer is imported and commissioned. (AU)

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