Quantized Water Access to the HIV-1 Protease Active Site as a Proposed Mechanism for Cooperative Mutations in Drug Affinity.
Summary of "Quantized Water Access to the HIV-1 Protease Active Site as a Proposed Mechanism for Cooperative Mutations in Drug Affinity."
The development of resistance to different drugs remains a major problem for a wide range of infections. In particular, combinations of specific mutations, which individually demonstrate no effect, exhibit significant cooperativity. Here we show that changes to the energy of ligand binding in different resistant HIV-1 proteases are correlated with the creation of water binding sites in the active site. This correlation is conserved across two drugs (ritonavir and lopinavir). We propose that individual mutations induce changes in flap packing that are insufficient to allow water binding but in combination allow access, leading to the observed cooperative resistance.
Affiliation
Centre for Computational Science, Department of Chemistry, UCL , London, U.K.
Journal Details
This article was published in the following journal.
Name: Biochemistry
ISSN: 1520-4995
Pages: 6487-9
Links
- PubMed Source: http://www.ncbi.nlm.nih.gov/pubmed/22866962
- DOI: http://dx.doi.org/10.1021/bi300432u
Medical and Biotech [MESH] Definitions
Protease La
A prokaryotic ATP-dependent protease that plays a role in the degradation of many abnormal proteins. It is a tetramer of 87-kDa subunits, each of which contains a proteolytic site and a ATP-binding site.
Phenytoin
An anticonvulsant that is used in a wide variety of seizures. It is also an anti-arrhythmic and a muscle relaxant. The mechanism of therapeutic action is not clear, although several cellular actions have been described including effects on ion channels, active transport, and general membrane stabilization. The mechanism of its muscle relaxant effect appears to involve a reduction in the sensitivity of muscle spindles to stretch. Phenytoin has been proposed for several other therapeutic uses, but its use has been limited by its many adverse effects and interactions with other drugs.
Saquinavir
An HIV protease inhibitor which acts as an analog of an HIV protease cleavage site. It is a highly specific inhibitor of HIV-1 and HIV-2 proteases.
Nonachlazine
Coronary vasodilator with a novel mechanism of action; proposed as antianginal agent.
Hiv Protease
Enzyme of the human immunodeficiency virus that is required for post-translational cleavage of gag and gag-pol precursor polyproteins into functional products needed for viral assembly. HIV protease is an aspartic protease encoded by the amino terminus of the pol gene.
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