title: Progress toward virtual screening for drug side effects.
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.
authors.affiliation: Department of Biochemistry, University of Iowa, Iowa City, Iowa, USA.
authors.forename: William M
authors.initials: WM
authors.lastname: Rockey
authors.forename: Adrian H
authors.initials: AH
authors.lastname: Elcock
mesh_terms: D000244:Adenosine Diphosphate / Q000737:chemistry / Q000378:metabolism; D000465:Algorithms; D001381:Azepines / Q000737:chemistry / Q000378:metabolism; D001549:Benzamides; D001665:Binding Sites; D019295:Computational Biology / Q000379:methods*; D003198:Computer Simulation; D016503:Drug Delivery Systems; D004791:Enzyme Inhibitors / Q000009:adverse effects / Q000737:chemistry* / Q000378:metabolism*; D006153:Guanosine Diphosphate / Q000737:chemistry / Q000378:metabolism; D000068877:Imatinib Mesylate; D008958:Models, Molecular; D010879:Piperazines / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D011494:Protein Kinases / Q000737:chemistry / Q000378:metabolism; D011743:Pyrimidines / Q000737:chemistry / Q000378:metabolism; D011758:Pyrroles / Q000737:chemistry / Q000378:metabolism; D011955:Receptors, Drug / Q000737:chemistry / Q000378:metabolism; D018048:Receptors, Purinergic P2 / Q000737:chemistry / Q000378:metabolism; D012680:Sensitivity and Specificity; D055672:Static Electricity
chemical_list: D001381:Azepines; D001549:Benzamides; D004791:Enzyme Inhibitors; D010879:Piperazines; D011743:Pyrimidines; D011758:Pyrroles; D011955:Receptors, Drug; D018048:Receptors, Purinergic P2; D006153:Guanosine Diphosphate; D000244:Adenosine Diphosphate; D000068877:Imatinib Mesylate; C107079:hymenialdisine; D011494:Protein Kinases