Linked Life Data

12852762

Source:http://linkedlifedata.com/resource/pubmed/id/12852762

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
15
pubmed:dateCreated
2003-7-10
pubmed:abstractText
The cyclin-dependent protein kinases are important targets in drug discovery because of their role in cell cycle regulation. In this computational study, we have applied a continuum solvent model to study the interactions between cyclin-dependent kinase 2 (CDK2) and analogues of the clinically tested anticancer agent flavopiridol. The continuum solvent model uses Coulomb's law to account for direct electrostatic interactions, solves the Poisson equation to obtain the electrostatic contributions to solvation energy, and calculates scaled solvent-accessible surface area to account for hydrophobic interactions. The computed free energy of binding gauges the strength of protein-ligand interactions. Our model was first validated through a study on the binding of a number of flavopiridol derivatives to CDK2, and its ability to identify potent inhibitors was observed. The model was then used to aid in the design of novel CDK2 inhibitors with the aid of a computational sensitivity analysis. Some of these hypothetical structures could be significantly more potent than the lead compound flavopiridol. We applied two approaches to gain insights into designing selective inhibitors. One relied on the comparative analysis of the binding pocket for several hundred protein kinases to identify the parts of a lead compound whose modifications might lead to selective compounds. The other was based on building and using homology models for energy calculations. The homology models appear to be able to classify ligand potency into groups but cannot yet give reliable quantitative results.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jul
pubmed:issn
0022-2623
pubmed:author
pubmed:issnType
Print
pubmed:day
17
pubmed:volume
46
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
3314-25
pubmed:dateRevised
2009-11-19
pubmed:meshHeading
pubmed:year
2003
pubmed:articleTitle
A computational model of binding thermodynamics: the design of cyclin-dependent kinase 2 inhibitors.
pubmed:affiliation
Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California 92093-0365, USA.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S., Research Support, U.S. Gov't, Non-P.H.S., Research Support, Non-U.S. Gov't