TOPS-MODE model of multiplexing neuroprotective effects of drugs and experimental-theoretic study of new 1,3-rasagiline derivatives potentially useful in neurodegenerative diseases

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

Authors

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

Journal

Title: Bioorganic and Medicinal Chemistry

Vol. 21

Pages: 1870-1879

ISSN: 0968-0896

Publisher: Elsevier

Indexing

ISI Web of Knowledge - 55 Citations

Scopus - 61 Citations

Scientific classification

FOS: Natural sciences > Chemical sciences

Other information

Authenticus ID: P-005-28A

DOI: 10.1016/j.bmc.2013.01.035

Abstract (EN): The interest on computational techniques for the discovery of neuroprotective drugs has increased due to recent fail of important clinical trials. In fact, there is a huge amount of data accumulated in public databases like CHEMBL with respect to structurally heterogeneous series of drugs, multiple assays, drug targets, and model organisms. However, there are no reports of multi-target or multiplexing Quantitative Structure-Property Relationships (mt-QSAR/mx-QSAR) models of these multiplexing assay outcomes reported in CHEMBL for neurotoxicity/neuroprotective effects of drugs. Accordingly, in this paper we develop the first mx-QSAR model for multiplexing assays of neurotoxicity/neuroprotective effects of drugs. We used the method TOPS-MODE to calculate the structural parameters of drugs. The best model found correctly classified 4393 out of 4915 total cases in both training and validation. This is representative of overall train and validation Accuracy, Sensitivity, and Specificity values near to 90%, 98%, and 80%, respectively. This dataset includes multiplexing assay endpoints of 2217 compounds. Every one compound was assayed in at least one out of 338 assays, which involved 148 molecular or cellular targets and 35 standard type measures in 11 model organisms (including human). The second aim of this work is the exemplification of the use of the new mx-QSAR model with a practical case of study. To this end, we obtained again by organic synthesis and reported, by the first time, experimental assays of the new 1,3-rasagiline derivatives 3 different tests: assay (1) in absence of neurotoxic agents, (2) in the presence of glutamate, and (3) in the presence of H2O2. The higher neuroprotective effects found for each one of these assays were for the stereoisomers of compound 7: compound 7b with protection = 23.4% in assay (1) and protection = 15.2% in assay (2); and for compound 7a with protection = 46.2% in assay (3). Interestingly, almost all compounds show protection values >10% in assay (3) but not in the other 2 assays,. After that, we used the mx-QSAR model to predict the more probable response of the new compounds in 559 unique pharmacological tests not carried out experimentally. The results obtained are very significant because they complement the pharmacological studies of these promising rasagiline derivatives. This work paves the way for further developments in the multi-target/multiplexing screening of large libraries of compounds potentially useful in the treatment of neurodegenerative diseases.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 10