In Silico Screening Identification of Fatty Acids and Fatty Acid Derivatives with Antiseizure Activity: In Vitro and In Vivo Validation

Barrionuevo, Emilia Mercedes; Peralta, Estefanía; Manzur De Nardi, Agustín; Monat, Juliana; Fallico, Maximiliano José; Llanos, Manuel Augusto; Gavernet, Luciana; Mustafá, Emilio Román; Martin, Pedro; Talevi, Alan

doi:10.3390/pharmaceutics16080996

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In Silico Screening Identification of Fatty Acids and Fatty Acid Derivatives with Antiseizure Activity: In Vitro and In Vivo Validation

by

Emilia Mercedes Barrionuevo

^1,2,

Estefanía Peralta

^1,2,

Agustín Manzur De Nardi

³

,

Juliana Monat

³

,

Maximiliano José Fallico

^1,2,

Manuel Augusto Llanos

^1,2,

Luciana Gavernet

^1,2,

Emilio Román Mustafá

⁴,

Pedro Martin

³ and

Alan Talevi

^1,2,*

¹

Laboratory of Bioactive Compound Research and Development (LIDeB), Faculty of Exact Sciences, National University of La Plata (UNLP), Blvd. 120 1489, La Plata 1900, Argentina

²

Argentinean National Council of Scientific and Technical Research (CONICET), CCT La Plata, La Plata 1900, Argentina

³

Instituto de Estudios Inmunológicos y Fisiopatológicos (IIFP), Universidad Nacional de La Plata–CICPBA–CONICET, Boulevard 120 no. 1489, La Plata 1900, Argentina

⁴

Electrophysiology Laboratory of the Multidisciplinary Institute of Cell Biology [Argentine Research Council (CONICET), Scientific Research Commission of the Province of Buenos Aires (CIC-PBA) and National University of La Plata (UNLP)], La Plata 1900, Argentina

^*

Author to whom correspondence should be addressed.

Pharmaceutics 2024, 16(8), 996; https://doi.org/10.3390/pharmaceutics16080996 (registering DOI)

Submission received: 12 June 2024 / Revised: 19 July 2024 / Accepted: 24 July 2024 / Published: 27 July 2024

(This article belongs to the Special Issue Computer-Aided Development: Recent Advances and Expectations)

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Abstract

High fat diets have been used as complementary treatments for seizure disorders for more than a century. Moreover, many fatty acids and derivatives, including the broad-spectrum antiseizure medication valproic acid, have been explored and used as pharmacological agents to treat epilepsy. In this work, we have explored the anticonvulsant potential of a large library of fatty acids and fatty acid derivatives, the LIPID MAPS Structure Database, using structure-based virtual screening to assess their ability to block the voltage-gated sodium channel 1.2 (NaV1.2), a validated target for antiseizure medications. Four of the resulting in silico hits were submitted for experimental confirmation using in vitro patch clamp experiments, and their protective role was evaluated in an acute mice seizure model, the Maximal Electroshock seizure model. These four compounds were found to protect mice against seizures. Two of them exhibited blocking effects on NaV1.2, CaV2.2, and CaV3.1.

Keywords: epilepsy; fatty acids; free fatty acids; molecular docking; molecular dynamics; NaV1.2; ketogenic diet; nutraceuticals; CaV2.2; CaV3.1

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MDPI and ACS Style

Barrionuevo, E.M.; Peralta, E.; Manzur De Nardi, A.; Monat, J.; Fallico, M.J.; Llanos, M.A.; Gavernet, L.; Mustafá, E.R.; Martin, P.; Talevi, A. In Silico Screening Identification of Fatty Acids and Fatty Acid Derivatives with Antiseizure Activity: In Vitro and In Vivo Validation. Pharmaceutics 2024, 16, 996. https://doi.org/10.3390/pharmaceutics16080996

AMA Style

Barrionuevo EM, Peralta E, Manzur De Nardi A, Monat J, Fallico MJ, Llanos MA, Gavernet L, Mustafá ER, Martin P, Talevi A. In Silico Screening Identification of Fatty Acids and Fatty Acid Derivatives with Antiseizure Activity: In Vitro and In Vivo Validation. Pharmaceutics. 2024; 16(8):996. https://doi.org/10.3390/pharmaceutics16080996

Chicago/Turabian Style

Barrionuevo, Emilia Mercedes, Estefanía Peralta, Agustín Manzur De Nardi, Juliana Monat, Maximiliano José Fallico, Manuel Augusto Llanos, Luciana Gavernet, Emilio Román Mustafá, Pedro Martin, and Alan Talevi. 2024. "In Silico Screening Identification of Fatty Acids and Fatty Acid Derivatives with Antiseizure Activity: In Vitro and In Vivo Validation" Pharmaceutics 16, no. 8: 996. https://doi.org/10.3390/pharmaceutics16080996

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In Silico Screening Identification of Fatty Acids and Fatty Acid Derivatives with Antiseizure Activity: In Vitro and In Vivo Validation

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