Discovering high-affinity ligands from the computationally predicted structures and affinities of small molecules bound to a target: A virtual screening approach

We describe a ‘virtual NMR screening’ method to assist in the design of inhibitors that occupy different sites within a target. We dock small molecules into the active site of an enzyme and score them. Keeping the tightest-binding lead fixed in space, we dock and score other small molecules in its presence. Using this approach, linker groups are used to join the compounds together to form a high-affinity inhibitor. We present validation of our computational approach by reproducing experimental results for FKBP and stromelysin. Docking simulations are not subject to experimental problems such as proteolysis, protein or compound insolubility, or enzyme size. Because docking is fast and our scoring method can distinguish between high- and low-affinity inhibitors, this docking procedure shows promise as integral part of a drug-design strategy.