| Title: |
Identification of Riluzole Derivatives as Novel Calmodulin Inhibitors with Neuroprotective Activity by a joint synthesis, biosensor, and computational guided strategy |
| Authors: |
Baltasar Marchueta, Maider; Llona, Leire; Alicante Martínez, Sara; Barbolla Cuadrado, Iratxe; García Ibarluzea, Markel; Ramis Cortés, Rafael; Salomon, Ane Miren; Fundora Ortiz, Brenda; Araujo Lombraña, Ariane; Muguruza Montero, Arantza; Núñez Viadero, Eider; Pérez Olea, Scarlett; Villanueva, Christian; Leonardo Liceranzu, Aritz; Arrasate Gil, Sonia; Sotomayor Anduiza, María Nuria; Villarroel, Alvaro; Bergara Jauregui, Aitor; Lete Expósito, María Esther; González Díaz, Humberto |
| Contributors: |
SPRI ELKARTEK |
| Publisher Information: |
Elsevier |
| Publication Year: |
2024 |
| Collection: |
ADDI: Repositorio Institucional de la Universidad del País Vasco / Euskal Herriko Unibertsitatea (UPV/EHU - Basque Country University) |
| Subject Terms: |
cheminformatics; machine learning; Calmodulin inhibitors; Riluzole analogs; docking; FRET biosensor; neurodegenerative diseases; biological assays |
| Description: |
The development of new molecules for the treatment of calmodulin related cardiovascular or neurodegenerative diseases is an interesting goal. In this work, we introduce a novel strategy with four main steps: (1) chemical synthesis of target molecules, (2) Förster Resonance Energy Transfer (FRET) biosensor development and in vitro biological assay of new derivatives, (3) Cheminformatics models development and in vivo activity prediction, and (4) Docking studies. This strategy is illustrated with a case study. Firstly, a series of 4-substituted Riluzole derivatives 1-3 were synthetized through a strategy that involves the construction of the 4-bromoriluzole framework and its further functionalization via palladium catalysis or organolithium chemistry. Next, a FRET biosensor for monitoring Ca2+-dependent CaM-ligands interactions has been developed and used for the in vitro assay of Riluzole derivatives. In particular, the best inhibition (80%) was observed for 4-methoxyphenylriluzole 2b. Besides, we trained and validated a new Networks Invariant, Information Fusion, Perturbation Theory, and Machine Learning (NIFPTML) model for predicting probability profiles of in vivo biological activity parameters in different regions of the brain. Next, we used this model to predict the in vivo activity of the compounds experimentally studied in vitro. Last, docking study conducted on Riluzole and its derivatives has provided valuable insights into their binding conformations with the target protein, involving calmodulin and the SK4 channel. This new combined strategy may be useful to reduce assay costs (animals, materials, time, and human resources) in the drug discovery process of calmodulin inhibitors. ; SPRI ELKARTEK (CardiCaM KK-2020/00110) // Gobierno Vasco / Eusko Jaurlaritza (IT1558-22) // Ministerio de Ciencia e Innovación (PID2019-104148GB-100, PID2021-128286NB-100, PID2022-137365NB-100 ) |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/pdf |
| Language: |
English |
| Relation: |
info:eu-repo/grantAgreement/MICINN/PID2019–104148GB-100; info:eu-repo/grantAgreement/MICINN/PID2021–128286NB-100; info:eu-repo/grantAgreement/MICINN/PID2022–137365NB-100; https://www.sciencedirect.com/science/article/pii/S0753332224004864; Biomedicine & Pharmacotherapy 174 : (2024) // Art. ID 116602; https://hdl.handle.net/10810/66971 |
| DOI: |
10.1016/j.biopha.2024.116602 |
| Availability: |
https://hdl.handle.net/10810/66971; https://doi.org/10.1016/j.biopha.2024.116602 |
| Rights: |
info:eu-repo/semantics/openAccess ; http://creativecommons.org/licenses/by-nc-nd/3.0/es/ ; © 2024 The Authors. Published by Elsevier Masson SAS. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
| Accession Number: |
edsbas.ADF6D1E4 |
| Database: |
BASE |