• This study provides the first in silico evaluation of secondary metabolites from Piper crocatum against key SARS-CoV-2 protein targets. • Crocatin A, Crocatin B, and stigmasterol were assessed using molecular docking, molecular dynamics simulations, and MMGBSA binding free energy analysis. • Stigmasterol showed the strongest predicted docking affinity, whereas Crocatin A exhibited a more balanced profile of binding stability and favorable pharmacokinetic properties. • The results support Piper crocatum as a potential source of plant-derived compounds for early-stage antiviral drug discovery. The SARS-CoV-2 pandemic continues to pose global health challenges. Although vaccines and antiviral agents are available, the identification of plant-derived compounds capable of modulating viral protein function remains important, particularly at the early stage of drug discovery. Secondary metabolites isolated from Red Betel ( Piper crocatum ) were evaluated for their predicted interactions with key SARS-CoV-2 proteins using an integrated in silico approach. Crocatin A, Crocatin B, and stigmasterol were subjected to molecular docking against three SARS-CoV-2 targets: the main protease (M pro /3CL pro ), non-structural protein 15 (NSP15), and papain-like protease (PL pro ). Docking reliability was assessed through protocol validation. Selected ligand–protein complexes were further evaluated using 100 ns molecular dynamics simulations, followed by RMSD, RMSF, and MMGBSA binding free energy analyses. Pharmacokinetic properties and drug-likeness were predicted using ADMET screening tools. Stigmasterol exhibited the strongest predicted docking affinity toward multiple targets; however, ADMET predictions revealed unfavorable characteristics, including excessive lipophilicity and lower predicted safety margins. Crocatin A demonstrated moderate docking affinity combined with more favorable pharmacokinetic profiles and the most balanced stability and binding energetics during molecular dynamics simulations. Crocatin B showed stable backbone interactions but weaker MMGBSA binding free energy compared to Crocatin A. The integrated in silico analysis suggests that Crocatin A exhibits the most balanced computational profile among the tested compounds when considering docking performance, molecular dynamics behavior, and pharmacokinetic properties. These findings indicate that secondary metabolites from Piper crocatum warrant further experimental validation as potential candidates for early-stage antiviral drug development rather than definitive antiviral leads.
Kurnia et al. (Sun,) studied this question.