Prediction of multi-target networks of neuroprotective compounds with entropy indices and synthesis, assay, and theoretical study of new asymmetric 1,2-rasagiline carbamates

• Published in: International journal of molecular sciences 2014-09, Vol.15 (9), p.17035-17064
• Main Authors: Romero Durán, Francisco J, Alonso, Nerea, Caamaño, Olga, García-Mera, Xerardo, Yañez, Matilde, Prado-Prado, Francisco J, González-Díaz, Humberto
• Format: Article
• Language: English
• Subjects: Algorithms; Animals; Asymmetry; Carbamates - chemical synthesis; Carbamates - pharmacology; Cell Survival; Cells, Cultured; Cerebral Cortex - cytology; Chemical synthesis; Databases, Pharmaceutical; Drug Evaluation, Preclinical - methods; Entropy; Glutamic Acid - pharmacology; Indans - pharmacology; Models, Chemical; Molecular Structure; Neurology; Neuroprotective Agents - pharmacology; Quantitative Structure-Activity Relationship; Rats
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms150917035

In a multi-target complex network, the links (L(ij)) represent the interactions between the drug (d(i)) and the target (t(j)), characterized by different experimental measures (K(i), K(m), IC50, etc.) obtained in pharmacological assays under diverse boundary conditions (c(j)). In this work, we handle Shannon entropy measures for developing a model encompassing a multi-target network of neuroprotective/neurotoxic compounds reported in the CHEMBL database. The model predicts correctly >8300 experimental outcomes with Accuracy, Specificity, and Sensitivity above 80%-90% on training and external validation series. Indeed, the model can calculate different outcomes for >30 experimental measures in >400 different experimental protocolsin relation with >150 molecular and cellular targets on 11 different organisms (including human). Hereafter, we reported by the first time the synthesis, characterization, and experimental assays of a new series of chiral 1,2-rasagiline carbamate derivatives not reported in previous works. The experimental tests included: (1) assay in absence of neurotoxic agents; (2) in the presence of glutamate; and (3) in the presence of H2O2. Lastly, we used the new Assessing Links with Moving Averages (ALMA)-entropy model to predict possible outcomes for the new compounds in a high number of pharmacological tests not carried out experimentally.