ISSN print edition: 0366-6352 ISSN electronic edition: 1336-9075 Registr. No.: MK SR 9/7 Published monthly

Identification of potential inhibitors of the E2 protein of Eastern equine encephalitis virus (EEEV) using molecular docking, density functional theory, and molecular dynamics simulations: an in silico approach

Iqra Naeem, Syed Sib Tul Hassan Shah, Zhechen Qi, Maria Bibi, and Syeda Saira Iqbal

Zhejiang Province Key Laboratory of Plant Secondary Metabolism and Regulation, College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou, China

E-mail: hassanshahsibtul@gmail.com

Received: 8 November 2024  Accepted: 22 February 2025

Abstract:

Emerging as a significant global health threat, Eastern equine encephalitis virus (EEEV) poses serious risks due to its neuroinvasive nature, unpredictable transmission dynamics, and the lack of available treatment. In this study, a screening was conducted using the Gold and Platinum Asinex drug library, containing 261,120 compounds, to identify potential inhibitors against the EEEV E2 glycoprotein. We employed molecular docking (AutoDock Vina 1.2.3), density functional theory (DFT) calculations (Gaussian 09 and GaussView 5.0), molecular dynamics (MD) simulations (Desmond software package), and MMGBSA analysis (Maestro tool), and this study aimed to screen a large compound library for the identification of promising drug candidates. Molecular docking of the screened compound after ADMET screening resulted in docking energy ranging from − 4.3 to − 8.1 kcal/mol, with two compounds exhibiting a docking energy of − 8.1 kcal/mol. In comparison, the reference compound, heparan sulfate, had a docking energy of − 6.5 kcal/mol. During DFT calculation, compound-1 exhibited an energy gap of 0.29667 eV, while compound-2 had a smaller gap of 0.16424 eV, suggesting that both have high chemical reactivity and reduced kinetic stability. Stable RMSD and RMSF profiles were observed during the MD simulation run, conducted over 100 ns. During the MD simulations, both compounds interacted with the key active site residues such as ARG84, HIS114, and ARG 119. The binding affinities of the ligands were estimated using MMGBSA, presented as semiquantitative scores, indicating that both compound-1 (− 9.3) and compound-2 (− 9.6) exhibited stronger predicted binding than the heparan sulfate (− 4.2). Based on in silico analyses, compound-1 [4-[3-[(4-tert-butylphenyl)methyl]-7-hydroxy-triazolo[5,4-d]pyrimidin-5-yl]-1-piperidyl]-morpholino-methanone and compound-2 (4S)-N-(4-Isopropylphenyl)-6-oxo-2-[4-(2-pyridinyl)-1-piperazinyl]-1,4,5,6-tetrahydro-4-pyrimidinecarboxamide are identified as promising candidates for E2 glycoprotein inhibition in Eastern equine encephalitis virus (EEEV). The screened compounds are worth testing in in vitro and in vivo experiments.

Graphical abstract

Keywords: Eastern equine encephalitis virus; E2 glycoprotein; In silico drug designing; Molecular docking; Molecular dynamics simulations

Full paper is available at www.springerlink.com.

DOI: 10.1007/s11696-025-03988-8

Chemical Papers 79 (5) 3065–3084 (2025)