Role of protein flexibility in the discovery of new drugs

Abstract

AbstractProteins 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.