Carbonic Anhydrase II as a Candidate Target of Mushroom-Derived Osteoclast Inhibitors: A Zinc-Coordination-Validated Docking Screen

10th International Conference on Scientific and Academic Research, Konya, Türkiye, 17 - 18 Ekim 2026, ss.198-205, (Tam Metin Bildiri)

Abstract – Osteoclasts resorb bone by acidifying a sealed lacuna, and carbonic anhydrase II supplies the

protons exported by the vacuolar H+-ATPase; its loss in humans causes osteopetrosis, placing it among

the few osteoclast effectors validated by human genetics. Reports that mushroom-derived metabolites

suppress osteoclast differentiation are phenotypic: of 98 records retrieved, only six assign the activity to a

defined molecular target and none a carbonic anhydrase, leaving engagement of the catalytic Zn(II) center

unexamined. Because empirical scoring functions do not treat metal coordination explicitly, this requires

a protocol validated for pose recovery and ligand ranking. In 115 contacts across 113 complexes the

donor atom lies 1.94 Å from the zinc and is nitrogen in 114, a geometry none of 2484 docked poses

reached. The baseline generated a near-native pose for 80% of held-out targets but ranked it first in 40%.

A coordination term degraded prediction at all twelve settings inside the search, but post hoc re-ranking

of the unchanged ensemble raised accuracy to 61.2% and roughly halved the median Zn–ligand deviation;

a parameter-free filter on deviation from 1.94 Å attains 58.8%, so the information resides in the

coordination distance itself. Retrospective discrimination largely reflected chemotype, not potency.

Across 18 metabolites, zinc-binding chemistry separated them: ergostane steroids hold their closest

oxygen 2.6–7.5 Å from the metal, whereas ganoderic acid DM and antcin K place a carboxylate oxygen

at 2.34 and 2.43 Å, within the 2.27–2.47 Å range of five clinical sulfonamides. Since carboxylates are

weak Zn(II) ligands relative to sulfonamides, this implies a low-potency interaction that may contribute

to, but cannot alone explain, the reported cellular activity.

Keywords – Osteoclast Acidification, Carbonic Anhydrase II, Zinc Coordination, Fungal Metabolites, Molecular Docking