• protein flexibility;
  • drug design;
  • local motions;
  • allostery;
  • MD simulations


Proteins have inherent flexibility, and this plays a critical role in a vast array of biological functions, including ligand binding. Structure-based drug design (SBDD) strategies incorporate biomolecular structures with computational methods to predict and optimize ligand–receptor complexes. However, these strategies largely involve using static protein snapshots derived by classical X-ray 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: 26–35, 2011. © 2010 Wiley-Liss, Inc.