title: Model for high-throughput screening of multitarget drugs in chemical neurosciences: synthesis, assay, and theoretic study of rasagiline carbamates.
abstract: 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.
authors.affiliation: Department of Organic Chemistry, Faculty of Pharmacy, University of Santiago de Compostela (USC) , 15782, Santiago de Compostela, Spain.
authors.forename: Nerea
authors.initials: N
authors.lastname: Alonso
authors.forename: Olga
authors.initials: O
authors.lastname: Caamaño
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Romero-Duran
authors.forename: Feng
authors.initials: F
authors.lastname: Luan
authors.forename: M Natália
authors.initials: MN
authors.lastname: D S Cordeiro
authors.forename: Matilde
authors.initials: M
authors.lastname: Yañez
authors.forename: Humberto
authors.initials: H
authors.lastname: González-Díaz
authors.forename: Xerardo
authors.initials: X
authors.lastname: García-Mera
mesh_terms: D000818:Animals; D002219:Carbamates / Q000737:chemistry*; D002986:Clinical Trials as Topic / Q000379:methods / Q000592:standards; D003198:Computer Simulation; D016503:Drug Delivery Systems / Q000379:methods; D018698:Glutamic Acid / Q000633:toxicity; D057166:High-Throughput Screening Assays / Q000379:methods*; D006801:Humans; D007189:Indans / Q000138:chemical synthesis / Q000737:chemistry*; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000633:toxicity; D021281:Quantitative Structure-Activity Relationship; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D013057:Spectrum Analysis; D013269:Stochastic Processes
chemical_list: D002219:Carbamates; D007189:Indans; D018696:Neuroprotective Agents; C031967:rasagiline; D018698:Glutamic Acid