Combating susceptibility to drug resistance: lessons from HIV-1 protease
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UMass Chan Affiliations
Department of Biochemistry and Molecular PharmacologyDocument Type
Journal ArticlePublication Date
2004-10-19Keywords
Binding SitesDrug Resistance, Viral
*Genetic Predisposition to Disease
HIV Protease
HIV Protease Inhibitors
Biochemistry, Biophysics, and Structural Biology
Pharmacology, Toxicology and Environmental Health
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Show full item recordAbstract
Drug resistance is a major obstacle in modern medicine. However, resistance is rarely considered in drug development and may inadvertently be facilitated, as many designed inhibitors contact residues that can mutate to confer resistance, without significantly impairing function. Contemporary drug design often ignores the detailed atomic basis for function and primarily focuses on disrupting the target's activity, which is necessary but not sufficient for developing a robust drug. In this study, we examine the impact of drug-resistant mutations in HIV-1 protease on substrate recognition and demonstrate that most primary active site mutations do not extensively contact substrates, but are critical to inhibitor binding. We propose a general, structure-based strategy to reduce the probability of drug resistance by designing inhibitors that interact only with those residues that are essential for function.Source
Chem Biol. 2004 Oct;11(10):1333-8. Link to article on publisher's siteDOI
10.1016/j.chembiol.2004.08.010Permanent Link to this Item
http://hdl.handle.net/20.500.14038/26145PubMed ID
15489160Related Resources
Link to Article in PubMedae974a485f413a2113503eed53cd6c53
10.1016/j.chembiol.2004.08.010