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