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Wybrane problemy projektowania substancji biologicznie aktywnych

Polański J.

Wiadomości Chemiczne

1999

[Z] 53, 1-2

1-16

Although most of the drugs have been discovered serendipitously the rational design of the molecules has been attempted from years. However, only the recent years brought a variety of new techniques providing unquestionably efficient procedures. In particular, the methodology of 2D and 3D quantitative structure activity relationships (QSAR) and combinatorial chemistry should be mentioned. In this review the basic methodology of the classical Hansch QSAR aproach has been briefly discussed. In general, classical two-dimensional QSAR fails to distinguish between stereoisomers. This fact inspired the development of the idea of 3D QSAR. Just the last year brought the concept of 4D QSAR covering quantitative description of conformational effects. On the other hand, the comparative molecular field analysis CoMFA, which is the most common 3D QSAR scheme, demands perfect alignment of the series of molecules analyzed. Moreover, the results critically depend upon the way of overlaying the molecules. The CoMFA and 4D QSAR analyses base on the statistical techniques of the partial least square (PLS) and cross-validation procedure. Both from the theoretical and practical points of view more flexible procedures for the alignment of molecules are needed. A comparative technique of self-organizing neutral network provides one of alternatives allowing for such more flexible visualization and quantitative analysis of molecular similarity. The problem of the molecules alignment can also be solved by the use of a new 2D QSAR technique, the so-called holographic QSAR (HQSAR) which uses fragmental coding of the molecule. Combinatorial chemistry is a method that puts together the randomness of screening and the rationality of design. The idea of combinatorial synthesis consists in the parallel synthesis of the set (combinatorial library) of compounds obtained simultaneously. Depending upon the technique used such libraries can be obtained as complex mixtures of the products of the defined composition or separate compounds. Although it is the diversity of molecular library created by combinatorial procedure that allows for increasing the probability of finding active analogs, combinatorial methods are far from brute randomness. The new methods for the description of the similarity of such libraries have been proposed. The newest trend represented by in vitro nucleic acid selection which is designed to mimic the Nature's evolutionary processes is probably one of the most interesting ideas in drug desing. Just recently this idea has been expanded to small organic molecules.