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Internet Electronic Journal of Molecular Design - IEJMD, ISSN 1538-6414, CODEN IEJMAT
| ABSTRACT - Internet Electron. J. Mol. Des. June 2006, Volume 5, Number 6, 306-319 |
Topological Virtual Screening and Pharmacological Test of Novel Cytostatic Drugs
María Teresa Llacer, Jorge Gálvez, Ramón García-Domenech, María José Gómez-Lechón, Carmina Más-Arcas, and Jesús Vicente de Julián-Ortiz
Internet Electron. J. Mol. Des. 2006, 5, 306-319
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Abstract:
The main goal of the present work is selecting new cytostatic lead
compounds through molecular topology. This is particularly
interesting since the finding of new therapeutic alternatives for
cancer continues to be a very difficult task as demonstrated by the
low number of lead drugs approved by the international agencies in
the later years in this field. Molecular topology, a formalism based
on describing the molecules as hydrogen-depleted graphs, as well
as linear discriminant analysis, a statistical tool capable to
distinguish between two or more categories or objects, have been
used to select new cytostatic compounds. All the selected
compounds were tested in vitro against two human cell cultures:
HepG2, hepatocellular carcinoma and HeLa (ATCC CCL2) cell
lines, corresponding to cervix epithelioid carcinoma. A
mathematical model comprised of one discriminant function has
been developed. The model is able to classify correctly 91.3% of
the compounds from the training set. Usnic acid stands among the
selected active compounds, showing significant anti-proliferative
activity on the two selected lines HepG2 and HeLa, with IC50
values of 1.0 and 1.1 μM, respectively. Caffeine showed also
significant anti-proliferative activity on HeLa cells. Other
compounds such as pyridoxine, atropine and chlortetracycline
show moderate inhibitory effect on the HeLa cell line. The results
confirm other previous results from our group, regarding the
usefulness of molecular graphs and topological indices as effective
tools to discover new cytostatic compounds, especially new leads.
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