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 receptor and ligand flexibility are discussed as well as promising new developments to generate conformationally diverse ensembles of a protein structure. The large variety of possible conformational changes in proteins on ligand binding is illustrated for the enzyme reverse transcriptase of HIV-1, which is an important drug target. Take home message: If the backbone conformation of the binding site does not change, current docking programs can perform well by taking side-chain reorientations into account only. Future progress to account for full target flexibility in docking requires both accurate prediction of the essential modes of backbone motion and improvements in scoring to enhance selectivity. Thus, the scoring function should realistically cover energetic and particularly entropic contributions to binding, which would allow more realistic estimates of binding free energies.