SYSTEMATIC SEARCH IN CONFORMATIONAL-ANALYSIS

The coupling of conformation to activity and reactivity is a widely ac cepted concept, and as such has driven the development of tools which execute conformational searches in rapid and robust fashion [T.F. Have l, Frog. Biophys. Molec. Biol., 56 (1991) 43-78; A.R. Leach, In Rev. C omput. Chem.; K.B. Lipkowitz and D.B. Boyd, Ed.; VCH Publishers, Inc.: New York, N.Y., 1991, Vol. II, pp. 1-55]. Among the aims of these met hods are the determination of a complete set of local minima from whic h the global energy minimum can be identified, or the generation of co nformations consistent with constraints derived from SAR or structural studies. Most methods fall into two broad categories: those which are random or stochastic, and those which are systematic. Yet another gro up consists of those which are based on heuristics and artificial inte lligence [A.R. Leach, K. Prout, D.P. Dolata, J. Comput. Chem. 11 (1990 ) 680-693]. The first category is typified by molecular dynamics [W.F. van Gunsteren and H.J.C. Berendsen, Angew. Chem. Int. Ed. Eng., 29 (1 990) 992-1023], Monte Carlo [M.P. Alien and D.J. Tildesley, Computer S imulation of Liquids, Oxford Science Publications, 1989], distance geo metry [J.M. Blaney and J.S. Dixon, in K.B. Lipkowitz and D.B. Boyd (Ed s.), Reviews in Computational Chemistry, VCH, New York, Vol. 5, pp. 29 9-335, 1994], and other approaches [M. Saunders, J. Comput. Chem., 10 (1989) 203-208] in which the path by which conformational space is exa mined is ideally completely random, but bounded by the geometries of c ovalent bond lengths and angles. In traditional systematic searches, t he variable to be examined, e.g. torsion angles, is divided into a reg ular grid. Each and every grid point is evaluated in a systematic fash ion to determine its validity. The path through the grid points is reg ular and defined. In principle, systematic search can, within the reso lution of the grid, identify all sterically allowed conformations of a molecule. Consequently, systematic search is an ideal tool for confor mational analysis because it is not path dependent and cannot become e ntrapped in local minima. In this article we review some of the basics of systematic search, algorithmic improvements that have enhanced its speed, and new developments that have increased its accuracy by movin g away from the limitations of a fixed torsional grid.