X-ray crystallographic structure of ABT-378 (lopinavir) bound to HIV-1 protease |
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Authors: | Stoll Vincent Qin Wenying Stewart Kent D Jakob Clarissa Park Chang Walter K Simmer R L Helfrich Rosalind Bussiere Dirk Kao J Kempf Dale Sham Hing L Norbeck Daniel W |
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Institution: | Department of Structural Biology, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064, USA. |
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Abstract: | The crystal structure of ABT-378 (lopinavir), bound to the active site of HIV-1 protease is described. A comparison with crystal structures of ritonavir, A-78791, and BILA-2450 shows some analogous features with previous reported compounds. A cyclic urea unit in the P(2) position of ABT-378 is novel and makes two bidentate hydrogen bonds with Asp 29 of HIV-1 protease. In addition, a previously unreported shift in the Gly 48 carbonyl position is observed. A discussion of the structural features responsible for its high potency against wild-type HIV protease is given along with an analysis of the effect of active site mutations on potency in in vitro assays. |
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