AutoDock's role in Developing the First Clinically-Approved HIV Integrase Inhibitor
Prof. J. Andrew McCammon and his colleagues used AutoDock and the Relaxed Complex Method to discover discover novel modes of inhibition of HIV integrase. Researchers at Merck Pharmaceutical Company have used McCammon's work to design new drugs that target integrase, which lead in October 2007 to the first clinically-approved HIV Integrase inhibitor: Isentress™ (raltegravir).
On October 12th, 2007, the pharmaceutical company Merck made a dramatic announcement in the treatment of multi-drug resistant HIV: the U.S. Food and Drug Administration (FDA) had granted accelerated approval for ISENTRESS™ (raltegravir) tablets for use in combination with other antiretroviral agents for the treatment of HIV-1 infection in treatment-experienced adult patients.
ISENTRESS is the first medicine to be approved in a new class of antiretroviral drugs called integrase inhibitors. ISENTRESS works by inhibiting the insertion of HIV DNA into human DNA by the integrase enzyme. Inhibiting integrase from performing this essential function limits the ability of the virus to replicate and infect new cells. There are drugs in use that inhibit two other enzymes critical to the HIV replication process - protease and reverse transcriptase - but ISENTRESS is the only drug approved that inhibits the integrase enzyme.
We are delighted to report that AutoDock played an early role in this discovery: Prof. J. Andrew McCammon and his colleagues, Julie R. Schames, Richard H. Henchman, Jay S. Siegel, Christoph A. Sotriffer, and Haihong Ni, used AutoDock in conjunction with the Relaxed Complex Method (1-3), developed by Jung-Hsin Lin, Alexander L. Perryman, Julie R. Schames and J. Andrew McCammon to discover novel modes of inhibition of HIV integrase (4). Researchers at Merck Pharmaceutical Company then used Prof. McCammon's and his colleagues' work to design new drugs that target integrase, which lead in October 2007 to the first clinically-approved HIV Integrase inhibitor: Isentress™ (raltegravir). Alexander L. Perryman is now a postdoctoral researcher in the Olson Laboratory.
A press release from the National Science Foundation on the early, fundamental work is at http://www.nsf.gov/discoveries/disc_summ.jsp?cntn_id=104280. This is based on reference 4, the 2004 J Med Chem paper that explicitly outlines the role of AutoDock.
A press release from Merck & Co on the recent FDA approval of the new drug is at http://www.merck.com/newsroom/press_releases/product/2007_1012.html
A representative news item (from the San Francisco Chronicle) is at http://www.sfgate.com/cgi-bin/article.cgi?file=/c/a/2007/10/13/MN4VSP4RQ.DTL
Relaxed Complex Method
1. Lin, J.H., A.L. Perryman, J.R. Schames, and J.A. McCammon, Computational drug design accommodating receptor flexibility: the relaxed complex scheme. J Am Chem Soc, 2002. 124(20): 5632-3.
2. Lin, J.H., A.L. Perryman, J.R. Schames, and J.A. McCammon, The relaxed complex method: Accommodating receptor flexibility for drug design with an improved scoring scheme. Biopolymers, 2003. 68(1): 47-62.
3. McCammon, J.A., Target flexibility in molecular recognition. Biochim Biophys Acta, 2005. 1754(1-2): 221-4.
AutoDock, the Relaxed Complex method, and HIV-1 Integrase
4. Schames, J.R., R.H. Henchman, J.S. Siegel, C.A. Sotriffer, H. Ni, and J.A. McCammon, Discovery of a novel binding trench in HIV integrase. J Med Chem, 2004. 47(8): 1879-81.