Potential inhibitors of Zika Virus Envelope Protein Through Molecular Docking, and Dynamics Simulation Analyses

Tayyeb, Jehad Zuhair and da Silva, Maria Karolaynne and Al-Mutairi, Aamal A. and Alharbi, Hanan M. and Khojah, Alaa A. and Bayıl, Imren and Alzahrani, Abdullah Yahya Abdullah and Tóth, Zsolt György and Oliveira, Jonas Ivan Nobre and Zaki, Magdi E.A. (2025) Potential inhibitors of Zika Virus Envelope Protein Through Molecular Docking, and Dynamics Simulation Analyses. VIRUS RESEARCH, 361. ISSN 0168-1702

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Abstract

Zika virus (ZIKV) infection remains a global health threat with no approved antivirals or vaccines to date, creating an urgent need for therapeutics targeting ZIKV. The viral envelope (E) protein is critical for host cell entry and represents a validated target for antiviral intervention. Here, we aimed to identify natural flavonoid compounds capable of inhibiting the ZIKV E protein using a dual-phase in silico screening strategy. First, we performed density functional theory (DFT) calculations to optimize the structures of nine candidate flavonoids and obtain quantum chemical descriptors (electronic properties); we also evaluated their drug-likeness and ADMET profiles. Second, we conducted molecular docking of these optimized flavonoids to the E protein, followed by hybrid quantum mechanics/molecular mechanics (QM/MM) refinement and 100 ns molecular dynamics (MD) simulations with principal component analysis (PCA) and MM-PBSA binding free energy calculations to assess binding interactions and complex stability. Docking identified quercetin, pinocembrin, and naringenin as the top binders, with binding energies of –8.3, –8.1, and –8.0 kcal/mol, respectively. These lead flavonoids also exhibited favorable pharmacokinetic properties, including high predicted gastrointestinal absorption, efficient clearance, and minimal toxicity risk (no carcinogenic or organ-specific alerts). Notably, pinocembrin’s complex demonstrated the greatest stability throughout a 100 ns MD simulation, maintaining a tightly bound conformation. In conclusion, quercetin, pinocembrin, and naringenin emerge as promising ZIKV E protein inhibitors with robust target engagement and favorable drug-like profiles. Their significant translational potential as antiviral candidates warrants further in vitro and in vivo studies to confirm efficacy and safety.

Tudományterület / tudományág

natural sciences > biological sciences

Faculty

Not relevant

Institution

Soproni Egyetem

Item Type:	Article
SWORD Depositor:	Teszt Sword
Depositing User:	Csaba Horváth
Identification Number:	MTMT:36340959
Date Deposited:	02 Oct 2025 09:09
Last Modified:	02 Oct 2025 09:09
URI:	http://publicatio.uni-sopron.hu/id/eprint/3745

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