Zoanthamine-type alkaloids display a wide spectrum of biological effects. This study aimed
to examine the inhibitory effects of norzoanthamine and its ten homologues of zoanthamine
class on human fibroblast collagenase by modeling a three-dimensional structure of the
ligands at collagenase using energy minimization, docking, molecular dynamics simulation
and MM-PB/GBSA binding free energy calculations. The results showed that zoanthamide,
zooxathellamine and enol-iminium form of norzoanthamine, with lower binding free energies
than other compounds, are potent inhibitors of collagenase. However, the enol-iminium form of
norzoanthamine showed a more inhibitory activity against collagenase than its keto form. This
suggests that it can be used for treatment of many diseases such as osteoporosis, autoimmune
diseases, and cancer. Zinc-binding residues such as His 118, His 122 and His 128 for hydrogen
bonds and Leu 81, Tyr 110, Val 115, Leu 126, Pro 138, Ser 139 for hydrophobic interactions
should be considered for designing an inhibitor for collagenase. Our theoretical results and
MM/GBSA binding free energy calculations are consistent with experimental studies.
Abbreviation
MD: Molecular dynamics; RMSD: Root mean square deviation; MM-PB/GBSA:
Molecular mechanics Poisson-Boltzmann/General Born surface area, DFT: density functional
theory, B3LYP: Becke, three-parameter, Lee-Yang-Parr, RESP: Restrained electrostatic surfacepotentia
