TITLE:
In Silico and in Vitro Analysis of Pyrazolone Derivatives against Zika Virus and Identification of Potential NS5 Methyltransferase Inhibitors by Molecular Docking
AUTHORS:
Luciene Soares Silva, Tiago Soares Barbosa, Maria Leonisa Sanchez-Nuñez, Aldenise Mont Serrat Rosa da Silva, Vitor Won-Held Rabelo, Leonardo dos Santos Corrêa Amorim, Leonardo Alves Miceli, Percilene Fazolin Vegi, Alice Bernardino, Helena Carla Castro, Izabel Christina Nunes de Palmer Paixão
KEYWORDS:
Zika, Pyrazolone, NS5, Methyltransferase, Antivirals
JOURNAL NAME:
Journal of Biosciences and Medicines,
Vol.12 No.7,
July
23,
2024
ABSTRACT: Zika virus (ZIKV), a mosquito-borne flavivirus, has been associated with benign infections for decades. However, it has become a public health concern due to its association with severe fetal and neurological complications. Although many efforts have been made to control ZIKV infection, approved vaccines or antiviral drugs are still lacking. Consequently, the development of new effective anti-ZIKV agents is urgently needed. In this context, we investigated the antiviral potential of pyrazolone derivatives against ZIKV replication using in silico and in vitro methods. The four pyrazolone derivatives evaluated (1a, 1b, 1c, and 1d) inhibited over 50% of ZIKV replication with low cytotoxicity. Among them, compound 1b exhibited the most potent activity (EC50 = 4.3 μM) and the highest selectivity (SI = 342). Mechanism of action studies indicated that these compounds act at early stages of virus replication, and compound 1b can also directly inactivate ZIKV particles. Molecular docking studies suggested that these compounds can bind to and block the activity of ZIKV NS5 methyltransferase. Finally, pharmacokinetic and toxicological predictions have reinforced the safety and drug-like profiles of these derivatives. In conclusion, the pyrazolone scaffold proved to be valuable for anti-ZIKV drug development, and the derivatives studied deserve further investigation.