Understanding HIV Protease Inhibitor Activity


The purpose of this experiment was to observe the interaction of three different compounds against the HIV-1 protease. These observations were used to compare the inhibitive effect the drugs have with HIV-1 protease. The compound used were between an FDA approved drug, saquinavir, a synthesized compound not yet in use, and a random medicinal drug compound, hydrocodone. The problem presented in this lab shows how the bonds between compounds and the protease molecule can inhibit the progressing of HIV. This experiment showed that the FDA drug had the greatest effect and the medicinal drug used had the least effect in inhibiting the HIV-1 protease.

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The use of molecular modeling is used in the development of drugs that aid in shaping the way that diseases are treated. The modeling of synthesized drugs and compounds can be used in seeing how each bond affects the absorption or inhibition of certain compound with enzymes and molecules within the human body (1). HIV, or Human Immunodeficiency Virus, is known as the virus that causes AIDS. HIV attacks the immune system and is contracted by contact with body fluids into mucous membrane such as intercourse, shared needles, or from mother to child during pregnancy. Aids is Acquired Immune Deficiency Syndrome, is the most advanced stage of HIV infection, and is a syndrome that eventually leads to death with having no cure. HIV/AIDS is a major epidemic in western countries such as the United States (2).

There are seven stages of life for HIV, binding, fusion, reverse transcription, integration, replication, assembly, and budding.  These steps to life are what make the spread of HIV so prevalent and how it replicates within our own cells. HIV-1 protease is an important part of that life cycle of HIV (3). HIV makes many proteins in a long piece put together with smaller portions. HIV-1 protease is in charge of cutting these long protein chains into the correct usable size. This is a critical step needed for the early life cycle when it becomes the young form of the HIV virus. Then, the proteins must be cut into the proper pieces to form the mature virus, which then infects more cells. These reactions must be timed perfectly to allow for proper assembly (4).

Currently, there are ten HIV protease inhibitors approved by the FDA those inhibitors are: atazanavir, amprenavir, darunavir, fosamprenavir, nelfinavir, saquinavir, indinavir, ritonavir, lopinavir, tipranavir (5). However, most of these drugs have harsh side-effects, especially when used over an extended period of time. Side effects include but are not limited to headache, fever, nausea, rash, itching, bloating, abdominal pain, peripheral neuropathy.


To begin this lab, download Chimera (https://www.cgl.ucsf.edu/chimera/download.html)4. Create a file on the computer hard drive to save all files related to this lab. Next, find the SMILE code for the FDA approved HIV protease inhibitor drug molecule A2 Saquinavir, through an online search and copy it. On Chimera, go to Tools, then Structure Editing, then Build Structures. Next, click on SMILES string and paste the string code (ctrl/v), Apply, and Close. This is when the structure should appear.

Next, go to Chimera Tools, Structure Editing, Minimize Structure. When the box appears, change steps to 1000, then minimize. When an Add Hydrogens pop-up appears, click ok, When the next pop up appears, change the charge to Gasteiger and click ok. Then click ok on the specific net charges pop-up. The A2 ligand should appear. Save ligand by using snipping tool to copy image and save into file used for this lab. 

Next on Chimera, select File, then fetch by ID, then PDB (biounit) type 1MUI (HIV-1 protease enzyme) then Fetch. Both the ligand and the HIV protease enzyme should appear.

Next select Tools, Surface/Binding Analysis, then Dock prep then click ok. When the Add hydrogen pop-up appears, click ok. When the Assign Chargers for dock prep pop-up appears, select Gasteiger and click ok. On the Specific Net charges pop-up click ok. Save the enzyme by using the snipping tool and save to the file for the lab.

Next, select Tools, then surface binding analysis, then AutoDock Vina. Next On Output file blank click browse, then save under C: molecular modeling/ file name: Final Dock Results, and set output location. On Output file blank click browse, and Select 1MUI protein pdb as the Receptor and the smile code, FDA drug ligand as the Ligand. Keep the AutoDock Vina pop-up open and click the Select tab, then residue, and find the ligand AB1 which is already attach to the 1MUI protein. Open the Action tab, then Atom bonds and then Delete.

Next fill the box with the given parameters: 13, 20, 30, and 19, 30, 30. Select Local under Executable location, click browse. then type in C:\Program Files (x86)\The Scripps Research Institute\Vina in the folder option and hit enter. Run as vina.exe, click ok, and select yes when the do you want to continue pop-up appears. The program will start to run. This will take few minutes to complete.

Once done, a popup window will appear called ViewDock., In ViewDock, select HBonds, then Add Count to Entire Receptor, select inter model, click ok. H bonds should be seen for every pose. Next in ViewDock window, click on the pose with highest number of H bonds (all).  All of the hydrogen bond connections between the HIV protease enzyme and the FDA approval drug should be seen. Record the maximum number of H bonds (all) and related score function. Repeat the same procedure for the published HIV protease compounds. Record the maximum number of H bonds (all) and related score function.


The purpose of this experiment was to observe the interaction of three different compounds against the HIV-1 protease. These observations were used to compare the interactions between an FDA approved drug, a synthesized compound not yet in use, and a random medicinal drug compound, hydrocodone. These compounds were used for molecular modeling. Simplified molecular input line entry (SMILE) codes were used to input into a modeling program, Chimera. HIV-1 protease was the receptor in this experiment. The results of this experiment showed that the FDA approved drug, saquinavir, had the most hydrogen bonds, 5, and the highest score function, meaning it had the most inhibitive effect and worked the best out of all three compounds. The in-lab synthesized compound had the same amount of hydrogen bonds, yet a slightly lower score function. However, the medicinal drug hydrocodone had the least effect with only 1 hydrogen bind and a very low score function. This experiment could be improved on by showing the mechanism in which the compounds connect to the HIV-1 protease to understand the inhibitive effects the compounds have. Applications of this experiment could be used to find better cancer treating drugs to inhibit the replication of cancer cells.


  1. Stone, J. E., Phillips, J. C., Freddolino, P. L., Hardy, D.J., Trabuco L.J., Schulten, K. (2007). Accelerating molecular modeling applications with graphics processors. Journal of Computational Chemistry. (2618-2640) doi:10.1002/jcc.20829
  2. Moss, A. R. Bacchetti, P., (1989) Natural history of HIV infection. AIDS. 55-62
  3. Cann, A. J., Karn, J., (1989) Molecular biology of HIV: new insights into the virus life-cycle. AIDS. 19-34. doi:10.1186/1742-4690-2-11
  4. E. O., (2001) HIV-1 Replication. Somatic Cell and Molecular Genetics. 13-33. doi:10.1023/A:1021070512287
  5. Lv, Z., Chu, Y., & Wang, Y. (2015). HIV protease inhibitors: a review of molecular selectivity and toxicity. HIV/AIDS 7, 95-104. doi:10.2147/HIV.S79956
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Understanding HIV Protease Inhibitor Activity. (2021, Apr 15). Retrieved May 19, 2022 , from

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