Linked Life Data

15183345

Source:http://linkedlifedata.com/resource/pubmed/id/15183345

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
9
pubmed:dateCreated
2004-6-8
pubmed:abstractText
Protease inhibitors are key components in the chemotherapy of HIV-1 infection. However, the long term efficacy of antiretroviral therapies is hampered by issues of patient compliance often associated with the presence of severe side effects, and above all by the appearance of drug resistance. The development of new protease inhibitors with high potency, low susceptibility to mutations and minimal affinity for unwanted targets is an urgent goal. The engineering of these adaptive inhibitors requires identification of the critical determinants of affinity, adaptability, and selectivity. Analysis of the binding database for existing clinical and experimental inhibitors has allowed us to address the following questions in a quantitative fashion: (1) Is there an optimal binding affinity? Or, are the highest affinity inhibitors necessarily the best inhibitors? (2) What is the dependence of optimal affinity on adaptability and selectivity? (3) What are the determinants of adaptability to mutations associated with drug resistance? (4) How selectivity against unwanted targets can be improved? It is shown that the optimal affinity is a function of the effective target concentration and the desired adaptability and selectivity factors. Furthermore, knowledge of the enthalpic and entropic contributions to the binding affinity to the wild type provides a way of anticipating the response of an inhibitor to mutations associated with drug resistance, and therefore, a valuable guideline for optimization.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Sep
pubmed:issn
1357-2725
pubmed:author
pubmed:copyrightInfo
Copyright 2004 Elsevier B.V.
pubmed:issnType
Print
pubmed:volume
36
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1787-99
pubmed:dateRevised
2007-11-14
pubmed:meshHeading
pubmed:year
2004
pubmed:articleTitle
Thermodynamic rules for the design of high affinity HIV-1 protease inhibitors with adaptability to mutations and high selectivity towards unwanted targets.
pubmed:affiliation
Department of Biology, Johns Hopkins University, 3400 North Charles, Baltimore, MD 21218, USA.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S., Research Support, U.S. Gov't, Non-P.H.S., Review