Final Report: Combining docking and free energy-based methods to improve virtual screening of drug candidates against HIV integrase

The title of this project is “Combining docking and free energy-based methods to improve virtual screening of drug candidates against HIV integrase.” Because HIV integrase is a key protein in the HIV-AIDS virus, the purpose of our research was to utilize docking, molecular dynamics simulation, and free energy calculation to computationally predict the success of HIV drug candidates in countering this protein. Similar to drug testing for other ailments, HIV drug testing and clinical trials typically require copious amounts of money, effort, and many, many years. With our work, we aim to use in-silico screening of drug candidates in order to focus the biomedical community’s time and resources on solely the most promising drug candidates for increased efficiency. Starting with software like Desmond from D.E. Shaw Research and then advancing towards using more powerful and advanced molecular modeling software, our research team collaborated in mastering techniques and determining the most promising HIV drug candidates. As our work continues to progress, we shall send our finalized results and data to Dr. Deng’s colleague at the University of Colorado for synthesis and further testing in a lab setting. Data analyses and results shall be published in an official scientific paper and also presented at the 2019 American Chemical Society national conference.

In-silico drug screening largely rested in the use and mastery of molecular docking. 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 and stable compound. Within the docking software, we can compare interaction energies of different 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 us evaluate its affinity. To accurately simulate these interactions as they occur within the human body, we instructed the software to create a body of water molecules surrounding the protein of interest. Using Command Line Interface (CLI) within Linux, we simulated how the protein exists in solution and proceeded to make observations and collect data regarding hydrogen bond strengths and other interactions between atoms. In particular, we shall continue by analyzing binding energy values and considering enthalpy, entropy, and other factors. Our team has not yet produced sufficient results for proper presentation, nonetheless we, under the tutelage of Dr. Deng, already have steady plans for the year ahead to advance our research using more advanced methods within the software as well as free-energy calculations in order to collect, finalize, and publish results in a timely manner.

The level of detail and intricacy that docking and molecular modeling require have made our work rather challenging. In the earliest stages, there were already issues with the software Desmond as it failed several simulations we tried to run. After troubleshooting and investigating possible sources of error, it became clear that there were some problems within the software itself that caused some simulations to “die.” Fortunately, Dr. Deng had planned on using Desmond for only the first few steps of our learning process, so we promptly switched to more advanced software. However, we must continue to work with caution and precision as similar issues and challenges will always arise within this type of research. Overall, mastering the various functions, formatting, and even the CLI within Linux proved challenging, and I am determined to continue putting in time and work to improve and excel.

My time conducting research with Dr. Deng this summer has enriched me through the lessons I learned and the challenges I encountered. This was the first time I ever delved into real, in-depth research, and I have been incredibly grateful for the experience. As a biochemistry major who excels in mathematics and biochemistry but has rather limited preliminary knowledge of coding and computing, I initially found this type of research somewhat intimidating. However, Dr. Deng has been excellent as a mentor and guide in teaching me about conducting good research, CLI, and the vast array of possibilities that molecular modeling presents as it relates to medicine and chemistry. I now find this field of academics to be exciting and intriguing, and the skills I have gained in problem-solving, coding, and modeling will surely be very helpful both now and in the future. Although I am currently a student on the pre-med track with plans of becoming a physician, I am now open to the idea of research not only in a lab setting but also from a more computationally-focused context. Pace University’s undergraduate student-faculty research program has given me a remarkable opportunity to enrich my knowledge and reinforce my desires to contribute to the world as part of the medical community; in particular, I now plan to continue conducting this research with Dr. Deng and likely take on similar medicine-oriented projects later in my academic career.

I am very eager to continue working with Dr. Deng and our team to collaborate, analyze, and finally see our work come to fruition in the future. It is a unique and splendid opportunity for a (formerly) first-year student like me to be given the chance to contribute my talents to important research so soon as the summer after freshman year. I have always dreamed of serving the community and changing lives as a physician, and I am extremely grateful to be able to get involved with medicine, contribute my talents towards the process of finding a cure for HIV-AIDS, and overall find a small way for me to potentially give back to the world. As we continue this project, I am determined to continue learning and to contribute to this incredibly important research in hopes of finding a cure for the over 30 million HIV-AIDS victims worldwide.

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