Progress toward virtual screening for drug side effects

William M Rockey; Adrian H Elcock

doi:10.1002/prot.10186

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Progress toward virtual screening for drug side effects

Journal article

Peer reviewed

Progress toward virtual screening for drug side effects

William M Rockey and Adrian H Elcock

Proteins, structure, function, and bioinformatics, Vol.48(4), pp.664-671

09/01/2002

DOI: 10.1002/prot.10186

PMID: 12211034

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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.

Protein Kinases - metabolism

Protein Kinases - chemistry

Piperazines - metabolism

Adenosine Diphosphate - chemistry

Piperazines - chemistry

Pyrimidines - chemistry

Pyrimidines - metabolism

Drug Delivery Systems

Receptors, Purinergic P2 - chemistry

Azepines - chemistry

Computer Simulation

Enzyme Inhibitors - chemistry

Sensitivity and Specificity

Guanosine Diphosphate - chemistry

Guanosine Diphosphate - metabolism

Binding Sites

Enzyme Inhibitors - adverse effects

Pyrroles - metabolism

Computational Biology - methods

Enzyme Inhibitors - metabolism

Models, Molecular

Static Electricity

Imatinib Mesylate

Receptors, Drug - metabolism

Receptors, Drug - chemistry

Algorithms

Receptors, Purinergic P2 - metabolism

Azepines - metabolism

Protein Binding

Pyrroles - chemistry

Adenosine Diphosphate - metabolism

Benzamides

Details

Title: Subtitle: Progress toward virtual screening for drug side effects
Creators: William M Rockey - Department of Biochemistry, University of Iowa, Iowa City, Iowa, USA
Adrian H Elcock
Resource Type: Journal article
Publication Details: Proteins, structure, function, and bioinformatics, Vol.48(4), pp.664-671
DOI: 10.1002/prot.10186
PMID: 12211034
NLM abbreviation: Proteins
ISSN: 0887-3585
eISSN: 1097-0134
Publisher: United States
Grant note: T32 GM007337 / NIGMS NIH HHS
Language: English
Date published: 09/01/2002
Academic Unit: Physics and Astronomy; Radiation Oncology; Biochemistry and Molecular Biology
Record Identifier: 9984025292902771

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