Abstract
Proteins have inherent flexibility, and this plays a critical role in a vast array of biological functions, including ligand binding. Structureβbased drug design (SBDD) strategies incorporate biomolecular structures with computational methods to predict and optimize ligandβreceptor complexes. However, these strategies largely involve using static protein snapshots derived by classical Xβray crystallography, and thus critical and valuable information on flexibility is completely absent. With a historical perspective, we highlight relevant fundamental aspects of the character and importance of the tapestry of flexibility in molecular recognition events, especially when a ligand binds to a protein. Knowledge of methods that can provide details of the full spectrum of flexibility in proteins is a requisite to laying the foundations for linking these concepts with the current algorithms employed in SBDD. Finally, we underline a number of examples that should urge the incorporation of protein flexibility in the industrial drug design pipeline. Drug Dev Res 72: 26β35, 2011. Β© 2010 WileyβLiss, Inc.