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Successful Virtual Screening of a Chemical Database for Farnesyltransferase Inhibitor Leads
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posted on 2000-02-10, 00:00 authored by Emanuele Perola, Kun Xu, Thomas M. Kollmeyer, Scott H. Kaufmann, Franklyn G. Prendergast, Yuan-Ping PangVirtual screening of chemical databases is an emerging approach in drug discovery that uses
computers to dock chemicals into the active site of a drug target to identify leads through
evaluation of binding affinities of the chemicals. However, there are concerns about the validity
and scope of the reported virtual screens due to lack of studies to show that randomly selected
chemicals are not equally active and due to the fact that metalloproteins were rarely used as
drug targets. We have performed a virtual screening of a chemical database to identify prototypic
inhibitors of farnesyltransferase (FT) with zinc present in the active site. Among the 21
compounds identified by computers, four inhibited FT in vitro with IC50 values in the range
from 25 to 100 μM. The most potent inhibitor also inhibited FT in human lung cancer cells. In
contrast, none of 21 randomly selected compounds have an IC50 lower than 100 μM. The results
demonstrate the validity of virtual screening and the feasibility of applications of this approach
to metalloprotein drug targets, such as matrix metalloproteinases, farnesyltransferase, and
HIV-1 integrase, for the treatments of cardiovascular diseases, cancers, and AIDS.
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binding affinitiesdrug targetsFarnesyltransferase Inhibitorsite100 μ MIC 50AIDSFTdock chemicalschemical databaseHIVmatrix metalloproteinasesdrug discoveryprototypic inhibitorsapproachfarnesyltransferase21 compoundsChemical Databasevaliditychemical databasesmetalloprotein drug targetsdrug targetIC 50 valuesVirtual screeningSuccessful Virtual Screeninglung cancer cells
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