Model for high-throughput screening of drug immunotoxicity--study of the anti-microbial G1 over peritoneal macrophages using flow cytometry.
Quantitative Structure-Activity (mt-QSAR) techniques may become an important tool for prediction of cytotoxicity and High-throughput Screening (HTS) of drugs to rationalize drug discovery process. In this work, we train and validate by the first time mt-QSAR model using TOPS-MODE approach to calculate drug molecular descriptors and Linear Discriminant Analysis (LDA) function. This model correctly classifies 8258 out of 9000 (Accuracy = 91.76%) multiplexing assay endpoints of 7903 drugs (including both train and validation series). Each endpoint correspond to one out of 1418 assays, 36 molecular and cellular targets, 46 standard type measures, in two possible organisms (human and mouse). After that, we determined experimentally, by the first time, the values of EC50 = 21.58 μg/mL and Cytotoxicity = 23.6% for the anti-microbial/anti-parasite drug G1 over Balb/C mouse peritoneal macrophages using flow cytometry. In addition, the model predicts for G1 only 7 positive endpoints out 1251 cytotoxicity assays (0.56% of probability of cytotoxicity in multiple assays). The results obtained complement the toxicological studies of this important drug. This work adds a new tool to the existing pool of few methods useful for multi-target HTS of ChEMBL and other libraries of compounds towards drug discovery.
Department of Organic Chemistry, Faculty of Pharmacy, USC, 15782 Santiago de Compostela, Spain; Centro de Investigación y Estudios Avanzados en Salud Animal, UAEM, 50200, Mexico.
Esvieta
E
Tenorio-Borroto
Centro de Investigación y Estudios Avanzados en Salud Animal, UAEM, 50200, Mexico.
Claudia G
CG
Peñuelas-Rivas
Centro de Investigación y Estudios Avanzados en Salud Animal, UAEM, 50200, Mexico.
Juan C
JC
Vásquez-Chagoyán
Chemical Bioactive Center (CBQ), Central University of Las Villas (UCLV), 50200 Santa Clara, Cuba.
Nilo
N
Castañedo
Biomedical Sciences Department, Health Science Division, University of Quintana Roo, 77039 Chetumal, Mexico.
Francisco J
FJ
Prado-Prado
Department of Organic Chemistry, Faculty of Pharmacy, USC, 15782 Santiago de Compostela, Spain.
Xerardo
X
García-Mera
Department of Organic Chemistry II, University of the Basque Country UPV/EHU, 48940 Leioa, Spain; IKERBASQUE, Basque Foundation for Science, 48011 Bilbao, Spain. Electronic address: humberto.gonzalezdiaz@ehu.es.
Humberto
H
González-Díaz
D000818:Animals; D000890:Anti-Infective Agents / Q000737:chemistry / Q000633:toxicity*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D016002:Discriminant Analysis; D005434:Flow Cytometry; D057166:High-Throughput Screening Assays; D006801:Humans; D008264:Macrophages / Q000166:cytology / Q000187:drug effects*; D051379:Mice; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D021281:Quantitative Structure-Activity Relationship
D000890:Anti-Infective Agents
ChEMBL; Chemical database of European Molecular Biology Laboratory; Drug immunotoxicity; Flow cytometry; High-throughput model; LDA; Macrophage; Multiplex assay endpoints; QSAR model; QSAR/QSTR; linear discriminant analysis; quantitative-structure/toxicity relationship