The cylinder moves or rotates within the lock until that fit configuration is reached and the ‘lock’ opens. That is, a device where the pointed teeth and notches on the key allow the pins and wafers in the lock to move up and down until they align with the shear line of the cylindrical grooves of the key. This concept paints a picture of an enzyme∷ligand interaction that is more akin to that of a ‘pin tumbler lock’. This ‘induced fit’ model conceptualizes the ‘lock’ (enzyme) as a dynamic entity and that the ‘key’ (substrate) modulates the shape of the ‘key hole’. Koshland’s suggestion was that active sites of enzymes are reshaped during interactions with substrate. Illustration of ‘Lock and Key’ (top), Induced fit (middle) and Combination Lock (bottom) model of protein-ligand binding interaction.īut, enzymes show conformational flexibility and, on that basis, Daniel Koshland proposed a modification to the ‘lock and key’ model. Herein, we briefly review contemporary approaches and suggest that future approaches treat protein-ligand docking problems in the context of a ‘combination lock’ system. 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. However, the complexities that confront accurate modeling of binding phenomena remain formidable. The last decade has witnessed more sophisticated molecular docking approaches to modeling protein-ligand binding and energetics. However, accurate predictions of binding pose and energetic remain challenging problems. In turn, molecular docking can reveal key elements in protein-ligand interactions-thereby enabling design of potent small molecule inhibitors directed against specific targets. 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. 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.
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