Computer assisted structure determination

Kahn, S.D., Booth, P.M., Waltho, J.P., Williams, D.H. Computer assisted structure determination, structure of the peptide Moroidin from Laportea moroides. J. Org. Chem. 54(8), 1901-1904 (1989)... 

Several databases exist today, containing hundreds of thousands of chemical-shift values, in particular for the H, and nuclei useful for polymer analysis and the shift information about the chemical environments of these individual nuclei. These data are an excellent basis for computer-assisted structure determination [23]. Databases of NMR spectra are suitable for three appUcafions. 

Since the early days of computer-assisted structure elucidation, the following three processes, in general, have been adopted (1) derivation of substructures from measured spectral data of an unknown (2) generation of all possible total structures based on the derived substructures (3) examination of candidate structures thus obtained (see Structure Determination by Computer-based Spectrum Interpretation). Any automated structure elucidation system for organic compounds... 

Even here, with well-established approaches, we see the influence of the information age. Employing computers to determine receptor structure and, thus, possible receptive blockers has become a useful tool in the drug discovery process. Computer-assisted drug synthesis has great potential. The revolution in this aspect of synthetic chemistry is analogous to the revolution that computers caused in the animation industry. Where once dozens of artists were necessary, computers have now replaced them, creating "life-like" animations that were not previously feasible. The same type of revolution will occur in the chemical drug synthetic industry. 

We determined the structure of human PNP by x-ray crystallography and used these results in combination with computer-assisted molecular modeling to design inhibitor candidates. We examined how well the shape and chemical... 

The past two decades have seen a marked change in the reporting of the application of various techniques to the determination of structure. Most papers relating to the synthesis of organic molecules now confine comments on UV and IR data to a minimum. While NMR data are presented in more detail, much 13C NMR spectral information is often presented simply as a catalogue of chemical shifts with little or no attempt at assignment. X-Ray structural determinations have become more commonplace and many papers now contain ORTEP representations of molecules. In addition, proposed structures are frequently supported by calculations and computer-assisted representations. 

In Chapter 4, David Lewis introduces computer-assisted methods in the evaluation of chemical toxicology. He points out that any substance can be toxic, and thus it is the dose of the substance that determines a toxic response. How, then, does one predict toxicity Lewis examines QSAR methods, pattern recognition techniques, computer modeling, and knowledge-based systems to answer this question. Ideally, one would like to assess toxicity of a structure before the compound is synthesized. To bring all this into focus, emphasis is placed on the cytochromes P450. 

Computer-assisted three-dimensional structure determination (CASD), which is appropriate for biological macromolecules such as proteins. 

The goal of the present study was to develop a computer-based cubic section model of the substrate binding domain of HLADH. It was considered that the Jones cubic section model could be refined by use of computer assisted substrate overlay in combination with kinetic data on a wide variety of substrates. As in the Jones approach we used the alcohol products as the surrogate substrate structures. Thus, we determined the low energy conformation of alcohols produced from ketones that have been reported to be reduced by HLADH and for which comparative kinetic data vs cyclohexanol could be calculated. As well, we determined the preferred conformations of all alcohols that would have been produced from ketones subjected to but failing to undergo HLADH reduction. These calculations utilised molecular mechanics (MACROMODEL) and yielded accurate co-ordinates for ali atoms in each alcohol. Where enantiomeric or stereoisomeric alcohols were produced or capable of production, the co-ordinates of each were calculated. 

Loftus, E. F., 8c Suppes, P. (1972). Structural variables that determine problem-solving difficulty in computer-assisted instruction. Journal of Educational Psychology, 63, 531-542. 

It is difficult to give an exhaustive list of the various possibilities which simplify analytical and structural MS studies, in particular in the fields of natural and biological products. We wish to stress, however, the particular importance of computer-assisted data processing, used to determine the structure of these compounds in a mixture and even in trace amounts [24],... 

The favored conformations of all eight l,2 5,6-di-0-isopropylidene-D-hexofuranoses have been evaluated by means of a computer-assisted, n.m.r. technique.102 It was demonstrated that the furanoid conformation is determined by the joint effects of the 1,2-O-isopropylidene part and the 5,6- tail unit. The ribo and lyxo structures were found to approximate to envelope conformations, whereas the arabino- and xylo-furanoses are less distorted, and approximate to twist conformers. 

Once an enzyme or receptor has been identified, ideally it should be isolated and characterized. A three-dimensional structure is very useful and can be determined from X-ray crystallography, NMR or by some other means which may include computer-assisted molecular modeling. The mechanism for the normal catalytic activity of the enzyme should be understood. This includes knowing the natural substrates, any natural inhibitors, and any coenzyme requirements. An i n vitro assay method must be developed to quantitatively test the effectiveness of potential inhibitors. At this point molecular modeling techniques can be used in the design process. 

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