Combining Docking and Free Energy-Based Methods to Improve Virtual Screening of Drug Candidates Against HIV Integrase

HIV-AIDS is a devastating disease that has a great impact on over 30 million people worldwide. A key protein in the virus is HIV integrase, and promising drugs to counter this disease should target this particular protein. Thus, under the guidance and leadership of Professor Nanjie Deng, the purpose of our team’s research is to collaboratively improve computational screening of drug candidates countering HIV integrase. Together with Dr. Deng, we shall utilize docking, molecular dynamics simulation, and free energy calculation to determine which drug molecules have the highest chances of success. Once we determine the most promising compounds, our results shall be sent to the University of Colorado so that Dr. Deng’s collaborator Professor Kvaratskhelia may synthesize these compounds in his lab for further testing. These compounds and published results shall be presented at the 2019 American Chemical Society national meeting.

Our research particularly aims to generate predictions of molecular compounds that may best bind HIV integrase. Consequently, the different methods and processes required for our research are key. Molecular docking is the process of predicting ligand conformation and orientation within a targeted binding site. Docking aims to find the ideal interaction energy between a specific receptor and ligand in order to create an ideal, stable resulting compound. Within the docking software, one can compare interaction energies of different forms/poses by using the software’s scoring function. For each possible pose, considering all conformational degrees of freedom, the scoring function gives a value that helps the researcher evaluate its affinity. We can increase efficiency by keeping the receptor rigid while keeping the ligand flexible; as a result, possible poses are more limited, and researchers have a narrowed down array of positions to evalulate. In general, this leads to researchers considering the binding energy values among other factors (e.g., enthalpy and entropy). Docking requires a rigorous amount of detail and specificity, however, thus this process can prove to be challenging. My particular role in our research lies in learning to run molecular dynamics simulation calculations in order to better observe and analyze binding for data collection.

We are determined to use our research to increase the efficiency and  success of HIV drug testing and production. I expect that the predicted compounds in our findings shall serve as potential potent HIV drug candidates, and we shall work to create results that could ultimately lead to the betterment of HIV treatment for victims of the deadly ailment around the world. With our research’s predictions and data, the clinical trial process for HIV drug candidates can be made most efficient since funds and time shall be focused on solely testing the very few, most promising candidates. Throughout my time in this research project, I hope to contribute my talents to our team’s success and immerse myself in a medical research environment; specifically, this shall enrich my knowledge and prepare myself for medical school and a future in the medical field and research. Furthermore, our research shall demonstrate the potential and utility of docking, molecular dynamics simulation, and free energy calculation for in-silico screening of drug candidates. For the benefit of mankind, we shall use our work to reveal modern medicine to a new set of possibilities and potential in drug production.

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