To advance techniques for screening large data sets of diverse structures for toxicologically active compounds, an algorithm was developed that is not dependent upon a predetermined and specified toxicophore or an alignment of conformers to a lead compound. Instead, the approach provides the means to identify and quantify specific global and local stereoelectronic characteristics associated with active compounds through a comparison of energeticallyreasonable conformer distributions for specific descriptors. To illustrate the algorithm, the stereoelectronic requirements associated with the binding affinity of 28 steroidal and non-steroidal ligands to the androgen receptor were defined. Common ranges of interatomic distances, atomic charges, and atom polarizabilities of oxygen atoms for conformers of the ligands with the highest affinity for the androgen receptor (most active) did not overlap with those identified for conformers with the lowest binding affinity (least active). Using a set of stereoelectronic parameters that provided a maximal measure of pairwise similarity among the conformers of the most active ligands, a model was developed to screen compounds for binding affinity. The model was capable of discriminating inactive ligands, as defined by a specified binding affinity threshold. This modeling technique could be a useful initial component in an integrated approach of employing computational and toxicological techniques in hazard identifications for large databases.

A new combinatorial approach to 3D molecular design is presented. Proceeding from atom-atom connectivity augmented by the type of atoms and multiplicity of chemical bonds, it provides an exhaustive generation of all stereoisomers, enantiomers, and conformers, corresponding to the given molecular topochemistry. The core of the system is the so called idea of "propagating 3D spanning tree". The latter is an acyclic 3D model of the molecular skeleton. During propagation, it loses its acyclic character by closure of rings and eventually transforms into a 3D molecular skeleton. A current bond of 3D-spanning tree is positioned in the space by

Simple and efficient algorithms are presented for detecting the full set of molecular symmetry operations (rotation and reflection), for identifying the respective symmetry elements, and for assigning the molecular point groups. All molecular symmetry point groups are available. The algorithms can be easily generalized for any three-dimensional structure that can be defined by a set of vertexes V(ν i ), edges (pairs of connected vertexes) E(ν i ν j ), and the Cartesian coordinates of the vertexes.

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A new approach called "dynamic" QSAR is introduced to enhance the exploration of active chemicals and relevant molecular descriptors. In contrast to conventional QSAR methods where chemical structure is described by a single, low energy conformer, "dynamic" QSAR simulates the multiplicity of 3-D molecular shapes that a molecule can assume in complex reaction environments. The core of the new methodology is the coupling of the 3DGEN algorithm which exhaustively generates conformers and a rule-based system to rapidly screen conformers for desired properties. Hypotheses regarding receptor shape and interaction mechanisms are conveniently incorporated into the screening algorithm. A full array of stereoelectronic parameters available to OASIS can be combined with conventional topological and physicochemical indices for all conformations and explored using a variety of mathematical and visualization techniques. The "dynamic" QSAR method is illustrated by modeling the acute toxicity of a series of unsaturated alcohols in fish.After some modifications. other 3D modeling packages (e.g., WI-ZARD) can also be suitable for employing dynamic QSAR analysis. However, a problem here is the fact that the existing conformer generators are based on the exploring conformational space