Computational Drug Design Accommodating Receptor Flexibility:  The Relaxed Complex Scheme

A novel computational methodology for drug design that accommodates receptor flexibility is described. This “relaxed-complex” method recognizes that ligand may bind to conformations that occur only rarely in the dynamics of the receptor. We have shown that the ligand−enzyme binding modes are very sensitive to the enzyme conformations, and our approach is capable of finding the best ligand−enzyme complexes. This new method serves as the computational analog of the experimental “SAR by NMR” and “tether” methods, which permit a building block approach for constructing a very potent drug.