Progress toward virtual screening for drug side effects

Publisher Website
Google Scholar
Abstract
The development and application of a computational protocol for conducting virtual screens of drug side interactions is described. A conventional drug‐docking algorithm (AutoDock) is used to conduct two separate studies. First, a series of docking simulations is performed by using guanosine diphosphate and adenosine diphosphate as prototype drugs with the goal of successfully differentiating known receptors from a large number of bait receptors. Using the electrostatic energy of the purine ring as a basis for discrimination allows the correct identification of receptors in blind studies with 100% specificity and 94% sensitivity. In a second study, similar methodology is used to investigate the binding of clinically relevant inhibitors (Gleevec, purvalanol A, and hymenialdisine) to a variety of protein kinase targets. Overall, excellent agreement between experimental and predicted preferences for kinase targets is obtained. An important conclusion from the latter study is that homology‐modeled structures of putative receptors may reasonably be used as targets for docking when directly solved crystal structures are not available. The prospects for routine application of the methodology as a means of identifying potential side interactions of candidate drugs are discussed. Proteins 2002;48:664–671.