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| Debananda Das, National Cancer Institute |
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Debananda Das grew up in various parts of Orissa, a state in eastern India. He studied in Ravenshaw College, and obtained his Masters in Science in Chemistry, from Indian Institute of Technology, Kanpur and a Masters in Technology in Chemical Analysis from Indian Institute of Technology, Delhi. He earned his Ph.D. in Chemistry from University of New Orleans in 1999, elucidating the structure and properties of small molecules using ab initio and density functional theory. As a postdoc with Bernie Brooks at the NIH, he worked on the double link atom method for partitioning QM/MM regions. After working as an Applications Scientist for Tripos, he joined the National Cancer Institute in early 2005 where he currently works on designing small molecule inhibitors, and in establishing the structure-function relationships of viral and cellular proteins involved in the replication of HIV.
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Structural Interactions of CCR5 with HIV-1 entry inhibitors
Debananda Das, National Cancer Institute
Debananda Das, Kenji Maeda, Philip Yin, Kiyoto Tsuchiya, Hiroaki Mitsuya
Affiliation: HIV & AIDS Malignancy Branch, National Cancer Institute, National Institute of Health; 10 Center Drive, Room 10S255 - MSC 1868; Bethesda, MD 20892-1868
Effective treatment of HIV continues to be a daunting challenge due to the emergence of drug resistant mutations in the target viral enzymes. CCR5 is a novel cellular target for the intervention of HIV replication. However, an X-ray or NMR structure of CCR5, a GPCR, does not exist. By combining the results of site directed mutagenesis experiments, homology modeling, and docking that accounted for the flexibility of the receptor side chains, we characterized the structural and molecular interactions of CCR5 with multiple CCR5 inhibitors active against R5 HIV-1 including a potent in vitro and in vivo CCR5 inhibitor aplaviroc. The quality of the structural model was evaluated by carrying out new saturation binding experiments by mutating CCR5 residues predicted to be important by the model. The structural model enabled us to precisely define the binding site of CCR5 inhibitors within CCR5 and elucidated the key binding site interactions responsible for the anti-viral activity of the inhibitors. We will discuss structure based drug design strategies that target specific residues of CCR5 to minimize toxic side effects.
Main points to be covered:
* Combination of site directed mutagenesis and molecular modeling can be a powerful tool for structure based drug design
* Iterative structure refinement that accounts for the flexibility of the receptor is important for generating a robust homology model.
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