In this chapter we review the use of 3-D pharmacophores in drug discovery. Recent advances are highlighted, including the application of pharmacophore descriptors generated both from ligands and protein binding sites. The application of 3-D pharmacophore fingerprints as molecular descriptors for similarity and diversity applications such as virtual screening, library design and QSAR is discussed . In addition, we highlight the quantification of structure-based diversity using site-derived fingerprints, and review virtual screening methods using both single refined hypotheses and the fingerprints of multiple potential hypotheses. Further, we discuss methods that take protein flexibility and molecular shape-into account. Each of the above techniques are reviewed with particular reference to the recent advances, advantages and challenges of each methodology.
Keywords: Pharmacophores in Drug Discovery, hydrogen bond donors, Prediction of ADME, ChemDiverse, potential tautomerism, DiR query, GRID analyses, Daichii factor, Hopkins statistic, MDDR ER active molecules