Model for High-Throughput Screening of Multitarget Drugs in Chemical Neurosciences: Synthesis, Assay, and Theoretic Study of Rasagiline Carbamates

• Type: Article in International Scientific Journal
• Date: 2013

Authors

Nerea Alonso (Author) Other; Olga Caamano (Author) Other; Francisco J Romero Duran (Author) Other; Feng Luan (Author) Other; Natalia N D S Cordeiro (Author) FCUP; Matilde Yanez (Author) Other; Humberto Gonzalez Diaz (Author) Other; Xerardo Garcia Mera (Author) Other

Journal

Title: Acs Chemical Neuroscience

Vol. 4

Pages: 1393-1403

ISSN: 1948-7193

Publisher: American Chemical Society

Indexing

ISI Web of Knowledge - 58 Citations

Scopus - 64 Citations

Scientific classification

FOS: Medical and Health sciences > Basic medicine

Other information

Authenticus ID: P-008-FDQ

DOI: 10.1021/cn400111n

Abstract (EN): 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 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.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 11