Nociceptin, a type of opiod receptor found in both the peripheral and central nervous systems, has recently been determined to be involved in the biochemistry of Post-Traumatic Stress Disorder (PTSD). Nociceptin stimulation (or lack thereof) is involved in stress, anxiety, learning, memory, and the pain response. Individuals with PTSD have altered nociceptive sensitivity, which, in turn, alters the body's ability to cope with stress, pain, and anxiety�whether physical or psychological. To create novel drug candidates that target nociceptin and aid in PTSD treatment, we used a variety of studies using the active site both empty and in complex with known ligands. We first mapped the charge distribution within the active site using Mulliken Atomic Charges, isolating pockets of high and low charge density. Electrostatic potential maps were also generated for the empty active site to visually assimilate this information. Known nociceptin ligands were used to identify residues within the active site that are especially important in ligand binding. Finally, novel drug candidates were designed to take advantage of the results found from the aforementioned studies and were tested with the same approach as the known ligands. This data will be correlated with EC50 data in QSAR analysis to draw conclusions about the relative potencies of these drug candidates. This project ultimately proposes several molecules to be further investigated for pharmacological use.

WFT and DFT studies of nociceptin receptor leading to novel PTSD drug candidates

248th National Meeting (2014)

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