Ligand-Based Drug Design (LBDD)

Ligand-based drug design is applied when the three-dimensional structure of the target is unavailable or unreliable, and instead derives design hypotheses...

Ligand-based drug design is applied when the three-dimensional structure of the target is unavailable or unreliable, and instead derives design hypotheses from the structures and biological activities of a set of known active compounds. Core LBDD methods include pharmacophore modelling, which identifies the common three-dimensional arrangement of chemical features (hydrogen-bond donors and acceptors, hydrophobic centres, and charged groups) shared by known active compounds; quantitative structure–activity relationship (QSAR) modelling, which statistically correlates measurable molecular descriptors with biological activity to build a predictive mathematical model; and molecular similarity searching, which identifies novel candidate compounds structurally or topologically similar to known actives. LBDD is particularly valuable for target classes, such as many G-protein-coupled receptors, for which high-resolution structural data has historically been difficult to obtain.