Potent Inhibition of Chikungunya Virus Entry by a Pyrazole–Benzene Derivative: A Computational Study Targeting the E1–E2 Glycoprotein Complex

The Chikungunya virus (CHIKV) continues to pose a significant global health challenge due to the absence of effective antiviral treatments and limited vaccine availability. This study employed a comprehensive in silico workflow, incorporating high-throughput virtual screening, binding free-energy calculations, ADMET (absorption, distribution, metabolism, excretion, and toxicity) analysis, and 200 ns molecular dynamics (MD) simulations, to identify new inhibitors targeting the E1-E2 glycoprotein complex, crucial for CHIKV entry and membrane fusion. Four promising candidates were identified from a library of 20,000 compounds, with CID 136801451 showing the most potent binding (docking score: -10.227; ΔG_bind: -51.53 kcal/mol). The top four compounds exhibited favorable ADMET profiles, meeting nearly all criteria. MD simulations confirmed stable binding and strong interactions between CID 136801451 and the E1-E2 complex, evidenced by consistently low RMSD values. These findings highlight CID 136801451 as a promising CHIKV entry inhibitor, warranting further in vitro and in vivo evaluation to advance the development of effective anti-CHIKV therapeutics.