Abstract
Accurate modeling of protein ligand binding is an important step in structure-based drug design, is a useful starting point for finding new lead compounds or drug candidates. The 'Lock and Key' concept of protein-ligand binding has dominated descriptions of these interactions, and has been effectively translated to computational molecular docking approaches. In turn, molecular docking can reveal key elements in protein-ligand interactions-thereby enabling design of potent small molecule inhibitors directed against specific targets. However, accurate predictions of binding pose and energetic remain challenging problems. The last decade has witnessed more sophisticated molecular docking approaches to modeling protein-ligand binding and energetics. However, the complexities that confront accurate modeling of binding phenomena remain formidable. Subtle recognition and discrimination patterns governed by three-dimensional features and microenvironments of the active site play vital roles in consolidating the key intermolecular interactions that mediates ligand binding. Herein, we briefly review contemporary approaches and suggest that future approaches treat protein-ligand docking problems in the context of a 'combination lock' system.
Highlights
In 1894, Emil Fischer suggested that the specificity of an enzyme towards its substrate is based on the two components exhibiting complementary geometric shapes that fit perfectly like a ‘key in a lock’
‘Induced fit’ is an attractive hypothesis as it accounts for why certain ligands are not substrates for an enzyme -- even though they seemingly satisfy the specific shape requirements to bind to the active site (Figure 1)
The first requirement for any successful docking simulation is to define an active site or binding pocket as this is a critical step in structure-based drug design, and provides a starting point for finding new lead compounds or drug candidates [8]
Summary
In 1894, Emil Fischer suggested that the specificity of an enzyme towards its substrate is based on the two components exhibiting complementary geometric shapes that fit perfectly like a ‘key in a lock’. Docking requires extensive sampling of conformational space for a ligand in the binding pocket of a protein and thereby generates large numbers of potential poses that orient a ligand within the active site. The first requirement for any successful docking simulation is to define an active site or binding pocket as this is a critical step in structure-based drug design, and provides a starting point for finding new lead compounds or drug candidates [8].
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