cn400111n_si_001.pdf (2.65 MB)
Model for High-Throughput Screening of Multitarget Drugs in Chemical Neurosciences: Synthesis, Assay, and Theoretic Study of Rasagiline Carbamates
journal contribution
posted on 2013-10-16, 00:00 authored by Nerea Alonso, Olga Caamaño, Francisco J. Romero-Duran, Feng Luan, M. Natália D. S. Cordeiro, Matilde Yañez, Humberto González-Díaz, Xerardo García-MeraThe disappointing results obtained
in recent clinical trials renew
the interest in experimental/computational techniques for the discovery
of neuroprotective drugs. In this context, multitarget or multiplexing
QSAR models (mt-QSAR/mx-QSAR) may help to predict neurotoxicity/neuroprotective
effects of drugs in multiple assays, on drug targets, and in model
organisms. In this work, we study a data set downloaded from CHEMBL;
each data point (>8000) contains the values of one out of 37 possible
measures of activity, 493 assays, 169 molecular or cellular targets,
and 11 different organisms (including human) for a given compound.
In this work, we introduce the first mx-QSAR model for neurotoxicity/neuroprotective
effects of drugs based on the MARCH-INSIDE (MI) method. First, we
used MI to calculate the stochastic spectral moments (structural descriptors)
of all compounds. Next, we found a model that classified correctly
2955 out of 3548 total cases in the training and validation series
with Accuracy, Sensitivity, and Specificity values > 80%. The model
also showed excellent results in Computational-Chemistry simulations
of High-Throughput Screening (CCHTS) experiments, with accuracy =
90.6% for 4671 positive cases. Next, we reported the synthesis, characterization,
and experimental assays of new rasagiline derivatives. We carried
out three different experimental tests: assay (1) in the absence of
neurotoxic agents, assay (2) in the presence of glutamate, and assay
(3) in the presence of H2O2. Compounds 11 with 27.4%, 8 with 11.6%, and 9 with 15.4% showed the highest neuroprotective effects in assays
(1), (2), and (3), respectively. After that, we used the mx-QSAR model
to carry out a CCHTS of the new compounds in >400 unique pharmacological
tests not carried out experimentally. Consequently, this model may
become a promising auxiliary tool for the discovery of new drugs for
the treatment of neurodegenerative diseases.
History
Usage metrics
Categories
Keywords
drug targetsvalidation seriesCCHTScompoundRasagiline CarbamatesTheneurodegenerative diseasesSpecificity valuesrasagiline derivativesMIH 2O Compounds 11Chemical Neurosciencesneuroprotective drugsMultitarget Drugsneuroprotective effects493 assaysCHEMBLmultiplexing QSAR modelsTheoretic Studymodel organisms
Licence
Exports
RefWorks
BibTeX
Ref. manager
Endnote
DataCite
NLM
DC