A systematic approach to finding new lead structures having biological activity

Abstract

The development of a new drug is an enormously largescale and expensive process. Thus, computer simulation methods become to play an increasing role in the development of new pharmacologically active compounds. Most of the commercial software presently used, comes from the U.S.; their deficits have become more and more obvious during the last years. Several methods have been developed in our project to alleviate these problems. The search for new lead structures starts with analyzing large databases of compounds (several hundreds of thousands up to several millions of compounds) zeroing into a few promising structures by increasing sophistication of structure representation. Due to the large number of chemical compounds, a systematic scheme for representing structures was developed: The starting point is the constitution, followed by calculation of the 3D structure, then including conformational flexibility. At each step, a variety of chemical properties can be taken into consideration. In addition, new programs have been developed for the treatment of conformational flexibility. The methods presented are also useful for other areas of application dealing with chemical information. Thus, it was shown that one of these new structure representations is suitable for treating problems in combinatorial synthesis. Neural networks and genetic algorithms are highly important for the investigation of the correlation between structure and biological activity. Complex relationships and huge amounts of data can be processed by these methods. Implementation of these procedures on highly parallel computers has proved that datasets of several hundreds of thousands of structures can be treated with acceptable computation times.