Structure-Based Virtual Screening and Computational Evaluation of Putative Mushroom-Associated Natural Compounds as...

Janus kinase 1 (JAK1) is a key controller and regulator of cytokinemediated immune responses and an effective therapeutic target in autoimmune and inflammatory diseases. In the present study, an in silico workflow was implemented to identify secondary metabolites of mushrooms as prospective JAK1-binding compounds. This integrated computational-aided drug discovery (CADD) approach was used to evaluate their binding affinity scores, interactions, pharmacokinetic properties, structural stability, toxicity, and electronic characteristics.

An in-silico workflow was employed by employing molecular docking against two JAK1 crystal structures (PDB IDs: 6DBN and 6N7A) in a focused virtual library, and then pharmacokinetic absorption, distribution, metabolism, and excretion (ADME) prediction, toxicity analysis, molecular dynamics (MD) simulation, MM/PBSA binding free energy estimation, and density functional theory (DFT) analysis were performed.

Various compounds, such as Vibralactone Z1, SF2738 B, and Lumichrome, showed rather promising docking scores compared to the reference inhibitor Tofacitinib at the ATP-binding pocket of JAK1. ADME profiling and toxicity modeling predicted acceptable oral drug-like properties and high gastrointestinal absorption for the selected candidates. Although Terreumol A produced the highest docking score against one JAK1 structure, integrated evaluation of docking performance, ADME characteristics, toxicity predictions, and drug-likeness properties identified Vibralactone Z1, Vibrolactone X, SF2738 B, and Lumichrome as the most promising overall lead compounds. Furthermore, MM/PBSA calculations suggested energetically favorable binding, particularly for the 6DBN-SF2738 B complex, while 200-ns molecular dynamics simulations demonstrated moderate structural stability of the selected ligand-protein complexes. DFT analysis showed that Lumichrome and SF2738B had lower HOMO-LUMO energy gaps and good electronic descriptors, indicating increased electronic flexibility in the catalytic pocket.

The integrated computational findings suggest that selected mushroom-derived metabolites possess favorable binding affinity, pharmacokinetic properties, structural stability, and electronic characteristics that support their potential as JAK1 inhibitor scaffolds. These structurally diverse natural compounds provide valuable starting points for the rational design and optimization of novel JAK1-targeted therapeutics. However, the findings are based entirely on computational predictions and should be interpreted as hypothetical until experimentally validated.

This CADD approach identified Vibralactone Z1, SF2738 B, and Lumichrome as the most promising and putative mushroom-derived lead compounds for JAK1 inhibition based on data presented in this study through computational analyses. These results highlight their potential for further drug development: biochemical, cellular, in vitro, and in vivo studies are required to confirm their inhibitory activity, safety, and therapeutic efficacy.