Application of topological descriptors in QSAR and drug design: history and new trends

Powerful methodologies for drug design and drug database screening and selection are presently available. Studies relating the structure of molecules to a property or a biological activity by means of statistical tools (QSPR and QSAR studies, respectively) are particularly relevant. An important point for this methodology is the use of good structural descriptors that are representative of the molecular features responsible for the relevant activity. Topological indices (TIs) are two-dimensional descriptors which take into account the internal atomic arrangement of compounds, and which encode in numerical form information about molecular size, shape, branching, presence of heteroatoms and multiple bonds. The usefulness of TIs in QSPR and QSAR studies has been extensively demonstrated, and they have also been used as a measure of structural similarity or diversity by their application to databases virtually generated by computer. In this article we will briefly review the history of TIs, their advantages and limitations with respect to other descriptors, and their possibilities in drug design and database selection. These applications rely on new computational techniques such as virtual combinatorial synthesis, virtual computational screening or inverse QSAR.