Structure‐Based Computational Discovery of Natural Inhibitors from <i>Piper longum</i> Against Monkeypox Virus E12 Protein

Abstract The recent surge in monkeypox (mpox) virus (MPXV) infections highlights the urgent need for effective therapeutic strategies. The E12 protein, which is critical for viral replication, represents a promising target for the development of antiviral drugs. This study utilized a comprehensive computational pipeline to identify potential inhibitors of MPXV E12 protein from bioactive compounds extracted from Piper longum , a traditional medicinal plant. The methodological approach included structure‐based virtual screening, ADMET profiling, molecular dynamics simulations, and binding free energy calculations. A virtual screening of 221 compounds revealed four promising hits, including CIDs 70695727, 25245913, 94577, and 101878852. These substances outperformed the reference compound and demonstrated notable interactions at the active site. These compounds underwent further evaluation through ADMET analysis, 200 ns MD simulations, and MM/PBSA calculations. The assessments revealed CID 94577 as the most promising candidate, demonstrating excellent binding affinity, desirable pharmacokinetic features, and consistent interactions throughout molecular dynamics simulations. This study identifies four lead compounds from Piper longum , emphasizing the therapeutic potential of natural compounds in antiviral drug discovery. Further experimental validation is required to validate their efficacy and elucidate their mechanism of action.