Molecular docking and pharmacophoric modelling of 1,5-disubstituted tetrazoles as inhibitors of two proteins present in
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ORIGINAL RESEARCH
Molecular docking and pharmacophoric modelling of 1,5‑disubstituted tetrazoles as inhibitors of two proteins present in cancer, the ABL and the mutated T315I kinase Erik Díaz‑Cervantes1 · Carlos J. Cortés‑García2 · Luis Chacón‑García2 · Abel Suárez‑Castro2 Received: 5 June 2020 / Accepted: 6 November 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract A docking study of a set of several 1,5-disubstituted tetrazoles compounds has been performed to predict the poses of some potential inhibitors of the Abelson tyrosine-protein kinase and the mutated Abelson tyrosine-protein kinase T315I. The study was conducted through Lamarckian genetic algorithms in Autodock4 package. Bayesian calculations were performed; specificity and sensitivity values as well as positive predicted values, and negative predicted values were calculated using a set of 99 known experimentally active ligands and 385 decoys for the Abelson tyrosine-protein kinase from the Directory of Useful Decoys database. Root mean square deviation values were calculated though the X-ray crystallographic data of the bioactive pose of imatinib as reference, and the pose obtained with the above methods. The obtained results show the importance of the protein interactions with the halogens present in some of these 1,5-disubstituted tetrazoles ligands, as well as the presence of some hydrophobic fragments, obtained via the pharmacophoric model, concluding that the eight novels 1,5-disubstituted tetrazoles compounds herein identified, could be effective inhibitors of Abelson tyrosine-protein kinase, using a docking calculations. Keywords Docking · Pharmacophore-model · 1,5-DS-T · ABL kinase · Mutant T315I · Anticancer
Introduction Chronic myelogenous leukemia (CML) is a human disease characterized by a translocation between chromosomes 9 and 22 into the c-abl locus of chromosome 9 and the bcr region of chromosome 22 (Ben-Neriah et al. 1986). Its incidence is 2 per 100,000 people each year and the common age of diagnosis of the disease is 50–55 (Von Bubnoff and Duyster 2010). Moreover, ABL tyrosine kinases constitute a family of proteins with the best-conserved branches of * Carlos J. Cortés‑García [email protected] * Abel Suárez‑Castro [email protected] 1
Departamento de Alimentos, Centro Interdisciplinario del Noreste (CINUG), Universidad de Guanajuato, 37975 Tierra Blanca, Guanajuato, Mexico
Laboratorio de Diseño Molecular, Instituto de Investigaciones Químico‑Biológicas, Universidad Michoacana de San Nicolás de Hidalgo, Ciudad Universitaria, C.P. 58033 Morelia, Michoacán, Mexico
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the tyrosine kinases. There are two types of ABL tyrosine kinases: ABL1, which is involved in repairing damage to nuclear DNA, and ABL2, is present in cytoskeletal remodeling (Colicelli 2011). ABL genes have been observed in a tumor gene in the Abelson murine lymphosarcoma virus (Abelson and Rabstein 1970). Patients with CML, express a BCR-ABL1 oncoprotein that enhances the tyrosine kinase activity of the cells, leading to dow
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