Successful virtual screening of a chemical database for farnesyltransferase inhibitor leads

Emanuele Perola, Kun Xu, Thomas M. Kollmeyer, Scott H Kaufmann, Franklyn G. Prendergast, Yuan-Ping Pang

Research output: Contribution to journalArticle

139 Citations (Scopus)

Abstract

Virtual 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.

Original languageEnglish (US)
Pages (from-to)401-408
Number of pages8
JournalJournal of Medicinal Chemistry
Volume43
Issue number3
DOIs
StatePublished - Feb 10 2000

Fingerprint

Chemical Databases
Farnesyltranstransferase
Screening
Metalloproteins
Inhibitory Concentration 50
Catalytic Domain
Pharmaceutical Preparations
Drug Discovery
Matrix Metalloproteinases
Docks
Reproducibility of Results
Zinc
Lung Neoplasms
Acquired Immunodeficiency Syndrome
Cardiovascular Diseases
Cells
Neoplasms

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Successful virtual screening of a chemical database for farnesyltransferase inhibitor leads. / Perola, Emanuele; Xu, Kun; Kollmeyer, Thomas M.; Kaufmann, Scott H; Prendergast, Franklyn G.; Pang, Yuan-Ping.

In: Journal of Medicinal Chemistry, Vol. 43, No. 3, 10.02.2000, p. 401-408.

Research output: Contribution to journalArticle

Perola, Emanuele ; Xu, Kun ; Kollmeyer, Thomas M. ; Kaufmann, Scott H ; Prendergast, Franklyn G. ; Pang, Yuan-Ping. / Successful virtual screening of a chemical database for farnesyltransferase inhibitor leads. In: Journal of Medicinal Chemistry. 2000 ; Vol. 43, No. 3. pp. 401-408.
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