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- Computational Analysis of a Mutated μ-opioid Receptor Bound to a Morphinan AntagonistMarques, Luiza Dias; Luthango, Philade; Wright, Bailee; Gregory, Logan (2023-07-21)Opium is a depressant drug, derived from the opium poppy (Papaver somniferum L.), and holds one of the earliest records of medicinal plant use. Deriva ves of opium, codeine and morphine, are extensively used in therapeu c pain relief treatments.The mu (μ) opioid receptor is produced from the OPRM1 gene and acts as the primary receptor for most opioid drugs, which are highly addic ve. Narcan is used to counter the effects of an opium overdose; if Narcan binds to the receptor more effec vely, its inhibitory effect will increase and it can bind more favorably than opium or opium deriva ves in the event of an overdose. Researchers know that differences in the receptors' structure and func on influence how the body responds to opioids. In this study, we mutated the Tryptophan-318 residue into an Arginine residue in order to observe whether it would result in a more ideal binding arrangement of narcan. We performed molecular docking in order to obtain the RMSD and affinity values for each predicted posi on of narcan with and without the inves gated muta on. On average, the Y318R μ-opioid receptor produced poses with higher binding affinity than the original protein. The op mum affinity value for the Y318R protein was also lower than that of the original protein. This led to the conclusion that muta ng Tryptophan-318 into Arginine enhances the binding of the morphinian antagonist to the μ-opioid receptor, making it more effec ve at countering the effects of an opium overdose. This research encourages further experimenta on regarding the muta on of addi onal residues and in turn the process of drug discovery can be improved.
- Huperzine A with Idebenone: Using Molecular Docking to analyze a potential Combination Therapy for Alzheimer’s Disease by Inhibition of the Acetylcholinesterase EnzymeSaleem Hashmi, Faeeza; Ramos, Laura; Bolorchuluun, Khishigbuyan; Hughes, Charli; Khojamuratova, Aynahan (2023-07-21)Those suffering from Alzheimer’s disease (AD) have low concentrations of Acetylcholine (ACh), a neurotransmitter involved in learning, memory, and muscle contraction. Acetylcholinesterase (AChE), a cholinergic type enzyme, plays a crucial role in concluding neurotransmission and degrading ACh. The accumulation of the AChE protein in AD patients results in decreased levels of ACh, and contributes to the buildup of amyloid-beta (Aβ) plaques that are crucial in the onset of AD. This study aims to examine how Idebenone could work as a potential inhibitor in addition to Huperzine A for AChE inhibition as a possible combination therapy for Alzheimer's Disease. Structure files of the inhibitors and AChE (PDB ID: 1VOT) were manipulated using PyMOL, GNINA, and Google Colab for molecular visualization and docking to find bond energies and possible ligand-protein interactions. The results confirmed that Idebenone has a significant binding affinity, though relatively lower than Huperzine A and in a different location, to be a useful component in this combination therapy due to its variety of interactions within AChE’s binding cavity including hydrogen bonds, hydrophobic and aromatic interactions. Huperzine A, with its stronger binding affinity, also exhibited positive interactions with amino acids surrounding the binding cavity of AChE, including hydrophobic and aromatic interactions. Most notably, the placement of each of these molecules did not significantly impact one another. Therefore, we can conclude that when used in conjunction, the two inhibitors target distinct locations in the wide binding pocket of AChE, and complement one another in the areas each can not cover alone. Their neuroprotective qualities also aid in the treatment of the disease. Future research could explore longer inhibitors to optimize binding within AChE's binding cavity and test the efficacy of this combination therapy on other neurodegenerative diseases involving cholinergic dysfunction.
- Sediment Diversion: Assessing the Potential of the Mississippi River to Mitigate Land LossSingh, Saranya; Metrouh, Nouha; Temirkhan, Arailym; Ngan, Tran Bao (2023)To avoid floods, engineers built long levees along the Mississippi river that are now preventing the Mississippi from depositing sediment into the surrounding floodplain and bays, and instead is diverting the sediment into the deeper parts of the Gulf of Mexico. Because sediment is not creating new land along the Mississippi, the compounded effects of a manmade rise in sea levels and the natural subsidence process are causing Louisiana to sink. A proposal by the Army Corps of Engineers, recently approved by the Louisiana state government, aims to redirect the Mississippi river towards coastal Louisiana and use sediment within the river to rebuild the floodplain. We contribute an analysis of the volume of sediment within the Mississippi and the volume of sediment required to regain the land lost since 1932. Using discharge and concentration data from the USGS, we conclude that, although there is ample sediment in the Mississippi to compensate for annual land loss, if the project is implemented in 2030, there is not enough sediment to regain all land lost since 1932 by 2090. We also calculate that from the year of implementation, it will take approximately 245 years to regain 50% of land loss since 1932, assuming that 50% of the river is successfully diverted.
- Utilizing Molecular Docking and Mutagenesis of Lys-233 into Ala-233 to Analyze the Effect on the Binding of the Morphinian Antagonist to the μ-Opioid ReceptorAgarwal, Samika; Henriques, Kyra; Halaby, Reine (2021-11-11)Opium is one of the oldest known medicines. Its derivatives, morphine and codeine, are among the most utilized therapeutic treatments to relieve severe pain (Manglik et al., 2012). Opium was originally used to create the first crystal structure of the μ-opioid receptor: the primary receptor for opioids that regulate the body’s response to pain (MedlinePlus, 2021). However, a method to increase the binding efficiency of its morphinian antagonist, β-funaltrexamine (β-FNA), is still unknown. In this study the residue, Lys-233, was mutated into Ala-233 to observe significant changes to binding. We used computational tools including AutoDock Vina (Eberhardt et al., 2021; Trott, et al., 2010) and PyMOL (The PyMOL Molecular Graphics System) to redock the ligand into the mutated protein. As a result, we found that the best RMSD value before mutation was 1.87 Å, but after mutation became 1.167 Å. On average, in the series of trials that occurred after the mutation, the nine poses produced better RMSD values. This led to the conclusion that mutating Lys-233 into Ala-233 enhances the binding of the morphinian antagonist to the μ-opioid receptor. Such research encourages the mutation of other opioid receptor residues in order to anticipate which variation provides the optimal result. This study suggests that many other combinations of mutations exist, through which the process of drug discovery can be improved.