Model for High-Throughput Screening of Multitarget
Drugs in Chemical Neurosciences: Synthesis, Assay, and Theoretic Study
of Rasagiline Carbamates
Nerea Alonso
Olga Caamaño
Francisco J. Romero-Duran
Feng Luan
M. Natália D. S. Cordeiro
Matilde Yañez
Humberto González-Díaz
Xerardo García-Mera
10.1021/cn400111n.s001
https://acs.figshare.com/articles/journal_contribution/Model_for_High_Throughput_Screening_of_Multitarget_Drugs_in_Chemical_Neurosciences_Synthesis_Assay_and_Theoretic_Study_of_Rasagiline_Carbamates/2365810
The 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 H<sub>2</sub>O<sub>2</sub>. Compounds <b>11</b> with 27.4%, <b>8</b> with 11.6%, and <b>9</b> 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.
2013-10-16 00:00:00
drug targets
validation series
CCHTS
compound
Rasagiline CarbamatesThe
neurodegenerative diseases
Specificity values
rasagiline derivatives
MI
H 2O Compounds 11
Chemical Neurosciences
neuroprotective drugs
Multitarget Drugs
neuroprotective effects
493 assays
CHEMBL
multiplexing QSAR models
Theoretic Study
model organisms