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Prediction of Positions of Active Compounds Makes It Possible To Increase Activity in Fragment-Based Drug Development
Biomedicinal Information Research Center (BIRC), National Institute of Advanced Industrial Science and Technology (AIST)/ 2-3-26, Aomi, Koto-ku, Tokyo 135-0064, Japan
Pharmaceutical Innovation Value Chain, BioGrid Center Kansai/ 1-4-2 Shinsenri-Higashimachi, Toyonaka, Osaka 560-0082, Japan
Received: 28 March 2011; in revised form: 17 May 2011 / Accepted: 20 May 2011 / Published: 20 May 2011
Abstract: We have developed a computational method that predicts the positions of active compounds, making it possible to increase activity as a fragment evolution strategy. We refer to the positions of these compounds as the active position. When an active fragment compound is found, the following lead generation process is performed, primarily to increase activity. In the current method, to predict the location of the active position, hydrogen atoms are replaced by small side chains, generating virtual compounds. These virtual compounds are docked to a target protein, and the docking scores (affinities) are examined. The hydrogen atom that gives the virtual compound with good affinity should correspond to the active position and it should be replaced to generate a lead compound. This method was found to work well, with the prediction of the active position being 2 times more efficient than random synthesis. In the current study, 15 examples of lead generation were examined. The probability of finding active positions among all hydrogen atoms was 26%, and the current method accurately predicted 60% of the active positions.
Keywords: FBDD; protein-compound docking; drug design; fragment growth; virtual screening; structure-based drug screening
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MDPI and ACS Style
Fukunishi, Y. Prediction of Positions of Active Compounds Makes It Possible To Increase Activity in Fragment-Based Drug Development. Pharmaceuticals 2011, 4, 758-769.
Fukunishi Y. Prediction of Positions of Active Compounds Makes It Possible To Increase Activity in Fragment-Based Drug Development. Pharmaceuticals. 2011; 4(5):758-769.
Fukunishi, Yoshifumi. 2011. "Prediction of Positions of Active Compounds Makes It Possible To Increase Activity in Fragment-Based Drug Development." Pharmaceuticals 4, no. 5: 758-769.