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 inh ibitors that occupy different sites within a target. We dock small molecule s into the active site of an enzyme and score them. Keeping the tightest-bi nding lead fixed in space, we dock and score other small molecules in its p resence. Using this approach, linker groups are used to join the compounds together to form a high-affinity inhibitor. We present validation of our co mputational approach by reproducing experimental results for FKBP and strom elysin. Docking simulations are not subject to experimental problems such a s proteolysis, protein or compound insolubility, or enzyme size. Because do cking 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.