The Selection of Novel Drugs for the Inhibition of Sterol Carrier Protein-2.

The endocannabinoid system has been increasingly understood to have important functions in the central nervous system, having a role in the regulation of stress, anxiety, metabolism, food intake, pain, and inflammation. Developing drugs to regulate this system is important not only for the treatment of diseases caused by imbalances of endocannabinoids within the body, such as migraines and even schizophrenia linked to endocannabinoids, but also generalized treatments for pain or stress. The Sterol Carrier Protein-2 (SCP-2) has been found to have a role in the regulation and transport of endocannabinoids within the body, and is therefore a target of interest for drug development. Previously a study screened small-molecule libraries for compounds that could possibly bind and inhibit human SCP-2 and computationally docked them with a human SCP-2 PDB structure, resulting in the identification of 4 promising compounds. However, when these compounds were tested against human SCP-2, they did not bind and behave as expected, concluding that our understanding of the structure of SCP-2 is not complete. Since this study, a new SCP-2 homology model has been developed that is theorized to better represent human SCP-2. This model will be used to reevaluate high-scoring potential inhibitors from the previous study to determine if there are any significant differences in binding energies, and to identify if a different set of compounds score higher. This will be carried out by conducting docking simulations using AutoDock Vina to determine the binding affinities of the previously screened compounds when docked to the new homology model. Additionally, the results of this study will be cross-referenced with a dynamics-based analysis of the homology model to determine if and how the dynamics of the proteins could be modified by ligand binding. This will be conducted using Essential Site Scanning Analysis (ESSA) which calculates how much each residue contributes to the global dynamics of the protein and can be used to predict allosteric sites, as well as ClustENMD which perturbs the structure to generate alternate conformations to identify cryptic pockets and critical dynamics. With these results, we will be able to give further insight into how SCP-2 can be inhibited as well as give a dynamics based analysis that could be useful in further studies. © FASEB.

Citation

Victoria Perez, Amber Sabin. The Selection of Novel Drugs for the Inhibition of Sterol Carrier Protein-2. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2022 May;36 Suppl 1

PMID: 35553734

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