Tackling the challenges posed by target flexibility in drug design.

Importance of the field: Current computational docking methods are often effective in predicting accurate drug-binding geometries in cases of relatively rigid target structures. However, binding of drug-like ligands to protein receptor molecules frequently involves or even requires conformational adaptation. Realistic prediction of ligand–receptor binding geometries and complex stability needs in many cases an appropriate inclusion of conformational changes, not only for the ligand, but also for the receptor molecule.Areas covered in this review: Recent approaches to efficiently account for target receptor flexibility during docking simulations are reviewed.What the reader will gain: The reader will gain insights into methods to efficiently treat protein side-chain flexibility and approaches for continuous adaptation of backbone conformations in pre-calculated essential or soft collective degrees of freedom. In addition, molecular dynamics or Monte Carlo based methods providing simultaneous inclusion of r...