Investigating OCT3-Mediated Buprenorphine Transport as a Mechanism for Salivary Accumulation and Oral Toxicity

Investigating OCT3-Mediated Buprenorphine Transport as a Mechanism for Salivary Accumulation and Oral Toxicity

Alvin Sherman Library

In this study we prepared a 3D printed model to better understand OCT3-mediated buprenorphine transport. Buprenorphine is a high affinity partial agonist at the mu-opioid receptor (μ-OR) and main component of Suboxone. It has a unique pharmacological profile that makes it effective for treating both pain and opioid use disorder (OUD) but has been linked to oral health issues such as dry-mouth and tooth decay. The exceptionally tight binding of suboxone to μ-OR allows for sustained receptor occupancy and reduced opioid misuse potential by patients. Recent evidence suggests that the Organic Cation Transporter 3 (OCT3), a membrane transporter expressed in salivary gland epithelial cells, facilitates drug excretion into salivary glands. We investigated this interaction and its role in mediating buprenorphine movement into saliva. Using molecular docking and structural modeling of human OCT3 crystal structures (PDBIDs: 7ZH0, 7ZH6, 7ZHA), buprenorphine binding interactions within the central-cavity of the transporter were analyzed. OCT3 has been found to transport substrates that share structural similarities with buprenorphine, including metformin, morphine, corticosterone, and decynium-22. Docking studies revealed that buprenorphine exhibits a high-binding affinity and specificity to OCT3. Although buprenorphine's calculated affinity (-8.376 kcal/mol) is slightly lower than corticosterone (-10.64 kcal/mol) and decynium-22 (-9.75 kcal/mol), its unique interactions with specific residues support the hypotheses that this molecule has specific strong interactions with OCT3. These buprenorphine-specific residues are hypothesized to form strong hydrophobic-interactions with the molecule, stabilizing polar interactions found with other substrates of the transporter in comparison to the other molecules.