Critical Analysis Example: Molecular Modeling Simulation Studies Reveal Inhibitors Against HPV E6 Protein

đź“ŚCategory: Biology, Health, Medicine, Science
đź“ŚWords: 431
đź“ŚPages: 2
đź“ŚPublished: 22 January 2022

In this paper, the researchers are trying to find a drug-based treatment for HPV, specifically by looking at the E6 protein through in silico (via computer) techniques. In HPV infected cells, E7 will degrade Retinoblastoma (the regulator of the cell cycle) causing abnormalities in the DNA or chromosomes and allowing HPV replication. E6 is also taken over by HPV to degrade p53 which is responsible for cell arrest or apoptosis once abnormalities are detected. Together E6 and E7 promote HPV replication and cell immortalization. Researchers found the E6 protein forms a complex and binds to a helical motif called LxxLL to recruit p53 and allow cell death. The hypothesis is that if they are able to find a ligand with drug like properties to bind to E6 the way LxxLL motif does, then they can evoke p53 activity to prevent cell immortalization. They want to find a ligand with drug likeness properties to make it more accessible and provide a less invasive method of treating cancer. 

First, 26 ligands were selected based on the structural similarity to ligands who are known to fight against HPV but have no evidence of fighting HPV themselves. Then, the ligands underwent ADME filtering which filtered based on drug-likeness properties. Next, the HPV-16 E6 protein was then modeled using Modeller v9.15 so they can later test the binding pockets with the ligands they select. Then, molecular dynamic simulations were used to test how E6 conformation changes under different conditions that could happen in a cell and trajectory analysis further investigated which conformations were best for drug targeting. Structure based virtual screening was used to see how well the E6 binding pocket bound to the ligands they selected from the previous tests and chose the ones with the lowest free binding energies. More tests for free binding energy were done through MM/PBSA and MM/GBSA. Finally, MD analysis concluded which ligands were the best candidates by being compared to their positive control luteolin. The most important experiment in the paper was the structure based virtual screening because it tested how well the three ligands they selected bound to the E6 protein and gave statistical data to compare each ligand based on free binding energies. This directly addresses the hypothesis and gives concrete reasons for the ligands they selected. I would agree with their results and conclusions because their logic to stimulate p53 makes sense. Since they were able to find ligands that would fit the requirements of the E6 pocket, I believe they would be able to find a solution similar to what they described if they moved to in vitro methods. It is unfortunate their research could not be backed up by in vitro studies, it would make a greater impact if they were able to prove their hypothesis to be correct in the lab.

+
x
Remember! This is just a sample.

You can order a custom paper by our expert writers

Order now
By clicking “Receive Essay”, you agree to our Terms of service and Privacy statement. We will occasionally send you account related emails.