Torreyunlignans (TA-D) are natural products isolated from the Yunnan Nutmeg Yew, <i>Torreya yunnanensis</i>. These compounds are the first reported naturally-occurring inhibitors of phosphodiesterase 9A (PDE9A), a high-affinity cGMP-specific enzyme. Previous research has indicated that PDE9A inhibitors are of therapeutic utility for the treatment of Alzheimer’s Disease and Diabetes mellitus. The active site of PDE9A contains key residues Y424, F56, F441, and the conserved Q453, as well as a hydrophobic clamp composed of the F441, V417, L421, and A452. Previous studies have shown that interactions with these residues and exploitation of the hydrophobic clamp are the most common among known PDE9A inhibitors, as well as its substrate. The potential therapeutic properties of TA-D make them a candidate for molecular docking and lead optimization studies. TA-D were modeled in PDE9A using AutoDock Vina and structural analogs of TA-D were developed. Computational predictions of absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties were also calculated to determine the drug candidate potential of TA-D and their structural analogs. Known inhibitors were also modeled in order to validate the computational analysis. Each showed the same active site orientation as their crystal structure, providing evidence that the AutoDock Vina modeling displayed an accurate representation of active site orientation. TA-D had higher affinity than the known inhibitors, which was improved in the structural analogs. Additionally, TA-D displayed interactions with all key residues aside from Q453. Of the high-affinity analogs (A), only A52 displayed Q453 interactions. Further work regarding the lead optimization of TA-D will be conducted to synthesize high-affinity analogs with drug-like pharmacokinetic attributes.

Molecular docking and lead optimization of torreyunlignans, phosphodiesterase 9A inhibitors

2019 Spring National Meeting

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