Reliable Prescreening of Candidate NerveAgent Prophylaxes via 3D QSAR
Abstract
Organophosphorus (OP) nerve agents are among the most toxic chemicals known to man and are notoriously easy to synthesize. As a result, their potential use against our military by insurgents, terrorists and other rogue groups remains a continuing threat. Therapeutics for countering OP toxicity exist, but do not adequately protect against some fast-acting agents (e.g., soman) without complementary support of prophylactic species. Some prophylactics do already exist, but may be responsible for unacceptable long-term health consequences. As a result, the search for safe, effective OP prophylactics remains of great interest. OP prophylactic design typically involves finding inhibitors of the acetylcholinesterase (AChE) active site (the target of OP toxicity) that bind strongly enough to prevent OP binding, but not so strongly as to be excessively toxic themselves. Searching such a balance through laboratory experiments alone is likely to entail an expensive, inefficient trial-and-error search. In order to expedite such efforts we have developed and applied computational quantitative structure-activity relationship models to the prediction of AChE-binding efficacy and toxicity for candidate prophylactics, identifying six strong inhibitor prospects (predicted to have sub-nanomolar Ki-values) from within the synthetically available chemicals of the NIH PubChem database.
Document Details
- Document Type
- Technical Report
- Publication Date
- Dec 31, 2005
- Accession Number
- ADA447364
Entities
People
- Gerald H. Lushington
- Jian-xin Guo
- Nora M. Wallace
Organizations
- University of Kansas