Identification and preliminary validation of potential endogenous targets for Maltanedienol

Abstract

Maltanedienol is the active principle of the alga, Padina pavonica. In vivo studies have shown that this species has the potential to produce and release a substance that has a positive effect on calcium fixation through its fronds. Maltanedienol has the utility in managing bone conditions such as osteoporosis. This study has two main aims: to identify the optimal biological targets for Maltanedienol, related to calcium deposition or bone remodelling and secondly, to study Maltanedienol’s interaction with these targets from an atomic perspective. A previous study utilising a ligand-based approach to identify endogenous targets for Maltanedienol discovered a potential of 59 candidates. The targets were filtered, based on their relationship to bone remodelling or calcium fixation, narrowing these to 36, of which only 26 were crystallographically described on the protein data bank. These 26 targets represented the study cohort. For each target, the small cognate molecule was extracted from its ligand binding pocket (LBP) and mutual affinity calculated in each case. Maltanedienol was subsequently docked into each target apo LBP and conformational analysis carried out. The conformer with the greatest peak height difference, between ligand binding affinity (pKd) and ligand binding energy (kcal/mol), was the optimal conformer and identified as the most likely bioactive scaffold based on high affinity and greatest stability. Seven of the 26 identified targets bound to Maltanedienol with higher affinity than their co-crystallised ligand. These targets were used for de novo design and formulated hypotheses regarding the biological activity of Maltanedienol. A 2D topology map was used to illustrate Maltanedienol’s optimal conformers interactions with its respective receptor active site. Additionally, this was used to exhibit the pharmacophoric moieties which were inhibiting the receptor’s active site. Different seeds were produced from each optimal conformer and allowed growth in each of their respective apo receptors. These seed structures were then filtered according to affinity and activity at their respective target LBP. Based on evidence from literature, a hypothesis of which of the selected receptors should be further studied as potential in vivo targets for Maltanedienol and mediators of calcium deposition in association with this molecule was made.