Project Report

The word "allosteric" refers to a change at one protein site, such as a drug binding or a mutation, that alters function at a different site. A classic example of allostery is hemoglobin, where binding of oxygen at one site helps oxygen bind better at the other three sites, so that hemoglobin takes up oxygen in the lungs and releases oxygen to the tissues. At the Center for Theoretical Biology at Peking University in Beijing, China, I used a computational approach I developed in graduate school to identify a novel site on an enzyme involved in inflammation for designing a novel drug that might work well in combination with aspirin or ibuprofen. In order to identify potential molecules that might bind to this site, I used molecular dynamics and molecular docking. In China, I had access to my host lab’s in-house drug-like molecule library, which consisted of Chinese drugs and natural products, such as those found in Chinese herbs and traditional medicine. I selected about twenty or so drug-like molecules in this library that I thought might bind to this site based on the docking results. A collaborator in my host lab made this enzyme in the lab and tested whether these molecules affected the enzyme activity. Interestingly, one of the molecules inhibited the enzyme non-competitively, suggesting that it might bind to the allosteric site. Ongoing work is in progress to computationally screen a larger number of molecules to find one that might activate the enzyme and be a significant milestone towards designing a new drug that work synergistically with aspirin or ibuprofen, so that lower doses of each drug could be used and minimize side-effects. Other broader impacts of this project included training, collaboration building, and cultural experiences. I learned about new methods to solve problems in systems biology and systems pharmacology, at one of the few labs in the world that has used computational systems biology to suggest new combination therapy drug targets. I also engaged in scientific outreach activities to disseminate my graduate research findings, including talks, lab visits, and conferences, including giving my first platform talk for an international conference, "Systems Biology: Past, Present, and Future", at Peking University. I also led my first workshop on computational chemistry software. My first-hand experiences of Chinese culture and academic culture will help me more effectively collaborate with Chinese nationals doing research in the US, and will help me build long-term collaborations with Chinese researchers, so that we can leverage our unique strengths to develop and apply novel computational tools towards discovering new pharmaceutical and biological therapeutics. Last Modified: 12/16/2011 Submitted by: Christopher L Mcclendon Part of my EAPSI experience involved a collaboration with scientists at National Institute of Biological Sciences (NIBS) in Beijing. This collaboration resulted in the following publication: Wan X, Ma Y, McClendon CL, Huang LJ-s, Huang N (2013) Ab Initio Modeling and Experimental Assessment of Janus Kinase 2 (JAK2) Kinase-Pseudokinase Complex Structure. PLoS Comput Biol 9(4): e1003022. doi:10.1371/journal.pcbi.1003022

National Science Foundation (NSF)
Office of International and Integrative Activities (IIA)
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Program Officer
Carter Kimsey
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Mcclendon Christopher L
San Francisco
United States
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