Comprehensive evaluation of potential EBOV inhibitors using advanced molecular modeling techniques: implications for anti-Ebola therapeutics and rational drug design

Abstract Background Ebola virus (EBOV) causes severe hemorrhagic fever outbreaks with high mortality rates, and currently there are no approved antiviral drugs. In this study, in silico (computational) techniques were applied to evaluate six small-molecule inhibitors—Latrunculin A, LJ001, CA-074, CA-074Me, U18666A, and Apilimod—focusing on drug-likeness, ADMET profiles, molecular docking, quantum chemical descriptors, and molecular dynamics simulations. Results Among the tested compounds, CA-074 proved to be the most promising candidate as it exhibited strong binding affinity to Cathepsin B (− 40.87 kcal/mol), an endosomal cysteine protease crucial for Ebola virus entry, as well as favorable ADMET properties and safety indicators such as absence of the human Ether-à-go-go-Related Gene (hERG) inhibition and mutagenic potential. CA-074 fulfilled the Lipinski and Veber rules with low plasma protein binding and a high unbound fraction, indicating improved bioavailability. The quantum descriptors indicated high chemical stability and low reactivity. Molecular dynamics confirmed the stability of the CA-074–Cathepsin B complex over 300 ns, with persistent hydrogen bonds and low flexibility in the binding pocket. Conclusion CA-074 has the potential to be a leading candidate for the treatment of EBOV. The comprehensive in silico strategy provides a valuable framework for accelerating early-stage antiviral drug discovery.