HIV protease-inhibitor complexes

Similarly, the techniques already described for determining the dynamics of ligands or macromolecules are also directly applicable to complexes. Again, specific examples are given in Section 4, including the use of relaxation data to study dynamics in HIV protease/inhibitor complexes and the use of dynamic lineshape studies for studying correlated ligand-protein dynamics in DHFR complexes. 

HIV-protease/inhibitor complexes have a molecular weight of approximately 22 kDa. Although NMR spectroscopy is well suited to determination of the structure of molecules in this size range, efforts to determine the solution structure of the complex were hampered by the fact that the protease undergoes rapid autocatalysis in solution. It required the development of potent inhibitors before NMR studies of the complex became feasible. The first solution structure of HIV-protease bound to the cyclic urea inhibitor DMP-323 (Fig. 25) was reported by Yamazaki in 1996.133 The protease exists as a homodimer. Each 99-residue monomer contains ten /3-strands and the dimer is stabilized by a four-stranded antiparallel /3-sheet formed by the N- and C-terminal strands of each monomer. The active site of the enzyme is formed at the interface, where each monomer contributes a catalytic triad (Asp25-Thr26-Gly27) that is... 

HIV protease/inhibitor complexes have a molecular weight of approximately 22 kDa. Although NMR spectroscopy is well suited to determination of the structure of molecules in this size range, efforts to determine the solution structure of the complex were hampered... 

Amprenavir (APV, Agenerase) is the most recently approved HIV protease inhibitor. It is smaller and stereochemically less complex than the other drugs in this class. Adsorption of this compound was found to be impaired by high fat meals. Common side effects of Amprenavir are nausea, vomiting, diarrhea, rash and a tingling sensation around the mouth. 

K. Appelt, Crystal Structures of HIV-1 protease inhibitor complexes, Prospect. Drug... 

Recently, the novel cyclooctylpyranone HIV protease inhibitor 193a was identified and an X-ray structure analysis of this inhibitor complexed with HIV-2 protease was obtained. This crystal structure was used to develop two strategies... 

Appelt K. Crystal structures of HIV-1 protease—inhibitor complexes. Perspectives in Drug Discovery and Design. 1993 1 23-48. 

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