title: Multi-Target Mining of Alzheimer Disease Proteome with Hansch's QSBR-Perturbation Theory and Experimental-Theoretic Study of New Thiophene Isosters of Rasagiline.
abstract: Hansch's model is a classic approach to Quantitative Structure-Binding Relationships (QSBR) problems in Pharmacology and Medicinal Chemistry. Hansch QSAR equations are used as input parameters of electronic structure and lipophilicity. In this work, we perform a review on Hansch's analysis. We also developed a new type of PT-QSBR Hansch's model based on Perturbation Theory (PT) and QSBR approach for a large number of drugs reported in CheMBL. The targets are proteins expressed by the Hippocampus region of the brain of Alzheimer Disease (AD) patients. The model predicted correctly 49312 out of 53783 negative perturbations (Specificity = 91.7%) and 16197 out of 21245 positive perturbations (Sensitivity = 76.2%) in training series. The model also predicted correctly 49312/53783 (91.7%) and 16197/21245 (76.2%) negative or positive perturbations in external validation series. We applied our model in theoretical-experimental studies of organic synthesis, pharmacological assay, and prediction of unmeasured results for a series of compounds similar to Rasagiline (compound of reference) with potential neuroprotection effect.
authors.affiliation: Department of Organic Chemistry, Faculty of Pharmacy, University of Santiago de Compostela (USC), 15782, Santiago de Compostela, Spain.
authors.forename: Paula
authors.initials: P
authors.lastname: Abeijon
authors.affiliation: Department of Organic Chemistry, Faculty of Pharmacy, University of Santiago de Compostela (USC), 15782, Santiago de Compostela, Spain.
authors.forename: Xerardo
authors.initials: X
authors.lastname: Garcia-Mera
authors.affiliation: Department of Organic Chemistry, Faculty of Pharmacy, University of Santiago de Compostela (USC), 15782, Santiago de Compostela, Spain.
authors.forename: Olga
authors.initials: O
authors.lastname: Caamano
authors.affiliation: Department of Pharmacology, Faculty of Pharmacy, University of Santiago de Compostela (USC), 15782, Santiago de Compostela, Spain.
authors.forename: Matilde
authors.initials: M
authors.lastname: Yanez
authors.affiliation: Department of Pharmacology, Faculty of Medicine, University of Basque Country (UPV/EHU), 48940, Leioa, Spain.
authors.forename: Edgar
authors.initials: E
authors.lastname: Lopez-Castro
authors.affiliation: IMQ Zorrotzaurre Clinic, 48014, Bilbao, Spain.
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Romero-Duran
authors.affiliation: Department of Organic Chemistry II, Faculty of Science and Technology, University of Basque Country (UPV/EHU), 48940, Leioa, Spain.
authors.forename: Humberto
authors.initials: H
authors.lastname: Gonzalez-Diaz
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D007189:Indans / Q000737:chemistry; D008962:Models, Theoretical; D018696:Neuroprotective Agents / Q000494:pharmacology; D020543:Proteome / Q000378:metabolism*; D021281:Quantitative Structure-Activity Relationship; D013876:Thiophenes / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D007189:Indans; D018696:Neuroprotective Agents; D020543:Proteome; D013876:Thiophenes; C031967:rasagiline
keywords: Alzheimer disease; QSBR models; drug-target binding; hippocampus proteome; neurodegenerative diseases; perturbation theory.; rasagiline derivatives