In Silico Evaluation of Gargalols A–C from the Mushroom Grifola gargal Against Osteoclast Targets: Heterogeneous Electrophiles and a Shared Phenotype
Munzur INTERNATIONAL SCIENTIFIC RESEARCH AND INNOVATION CONGRESS - IV, Tunceli, Türkiye, 3 - 04 Kasım 2026, ss.1-8, (Tam Metin Bildiri)
- Yayın Türü: Bildiri / Tam Metin Bildiri
- Basıldığı Şehir: Tunceli
- Basıldığı Ülke: Türkiye
- Sayfa Sayıları: ss.1-8
- Trakya Üniversitesi Adresli: Evet
Özet
Bone resorption is set by the differentiation of monocyte-macrophage-derived osteoclasts and their capacity to dissolve mineralised matrix. Gargalols A, B and C, isolated from the mushroom Grifola gargal, suppress osteoclast differentiation without cytotoxicity in the same assay, indicating that they act on the differentiation programme rather than by depleting precursor viability. The three compounds share a C28 ergostane scaffold but differ in their electrophilic groups: gargalol A has no Michael acceptor and only an epoxide, gargalol B an enone and an endoperoxide, and gargalol C an enone and an epoxide. This heterogeneity provides a control internal to the series for testing whether the shared phenotype arises from a shared covalent reactivity. The compounds were evaluated against a panel of nine druggable effectors representing distinct steps of osteoclast function: cathepsin K, which degrades collagen within the resorption lacuna, with the related cysteine proteases cathepsins L, S and B; carbonic anhydrase II, which supplies protons for ruffled-border acidification; MMP-9, which remodels the organic matrix; c-Src, which governs sealing-zone assembly; CSF1R, which sustains precursor proliferation; and RORγt, acting through the Th17/IL-17 axis. Before any test compound was examined, every receptor was validated by redocking its co-crystallised ligand, and seven of nine reproduced the crystallographic binding mode below 2 Å. The global electrophilicity index from GFN2-xTB spans 6.5 to 16.3 eV, a 2.5-fold range. Despite this, binding behaviour was indistinguishable from that of ergosterol, the non-electrophilic fungal sterol (Wilcoxon p = 0.681 over 21 matched comparisons; median difference 0.00 kcal/mol), and relative affinity at cathepsin K showed no monotonic relationship with electrophilicity. Approach geometry to the catalytic cysteine was measured over 288 electrophilic centres: only 13 came within 4.5 Å and all were epoxide carbons, while no enone β-carbon and no peroxide oxygen reached that distance. None of the proximal epoxides came within 50° of the anti geometry required for ring opening. Under the sampling and scoring conditions used, the shared osteoclast-suppressing activity is therefore not explained by direct inhibition of any classical resorptive effector in this panel.
Keywords: gargalol, Grifola gargal, osteoclast, molecular docking, electrophilicity, cathepsin K, epoxide