Rapid screening for HIV-1 protease inhibitor leads through X-ray diffraction.
Knowledge of the three-dimensional structures of HIV-1 protease and of its complexes with various inhibitors has played a key role in development of drugs against AIDS. Hexagonal crystals of unliganded tethered HIV-1 protease in which the enzyme conformation is identical to its ligand-bound state can be used in combination with the soaking method in order to identify potential inhibitor leads via X-ray diffraction. The advantages of the soaking method are the generality of application and the rapidity of structure determination for iterative structure-based drug design. Structures of two ligand complexes with HIV-1 protease determined using this method are shown to be very similar to the structures obtained earlier via co-crystallization.
Pillai
Bindu
B
Solid State Physics Division, Bhabha Atomic Research Centre, Trombay, Mumbai, India.
Kannan
K K
KK
Bhat
S V
SV
Hosur
M V
MV
D019943:Amino Acid Substitution / Q000235:genetics; D000925:Anticoagulants / Q000737:chemistry*; D020134:Catalytic Domain; D003374:Coumarins / Q000737:chemistry*; D018360:Crystallography, X-Ray; D016333:HIV Protease / Q000737:chemistry* / Q000235:genetics; D017320:HIV Protease Inhibitors / Q000737:chemistry*; D006860:Hydrogen Bonding; D008024:Ligands; D016297:Mutagenesis, Site-Directed; D010436:Pepstatins / Q000737:chemistry*; D017434:Protein Structure, Tertiary
D000925:Anticoagulants; D003374:Coumarins; D017320:HIV Protease Inhibitors; D008024:Ligands; D010436:Pepstatins; C014195:Streptomyces pepsin inhibitor; D016333:HIV Protease