2QI3

Crystal structure of protease inhibitor, MIT-2-AD94 in complex with wild type HIV-1 protease

Summary for 2QI3

• Entry DOI: 10.2210/pdb2qi3/pdb
• Related: 2QHY 2QHZ 2QI0 2QI1 2QI4 2QI5 2QI6 2QI7
• Descriptor: Protease, PHOSPHATE ION, (2S)-N-[(1S,2R)-3-{(1,3-BENZOTHIAZOL-6-YLSULFONYL)[(2S)-2-METHYLBUTYL]AMINO}-1-BENZYL-2-HYDROXYPROPYL]-2-HYDROXY-3-METHYLBUTANAMIDE, ... (4 entities in total)
• Functional Keywords: drug design, hiv-1 protease, protease inhibitors, hydrolase
• Biological source: Human immunodeficiency virus 1
• Total number of polymer chains: 2
• Total formula weight: 22369.25

Authors

Nalam, M.N.L.,Schiffer, C.A. (deposition date: 2007-07-03, release date: 2008-04-22, Last modification date: 2023-08-30)

Primary citation

Altman, M.D.,Ali, A.,Reddy, G.S.,Nalam, M.N.,Anjum, S.G.,Cao, H.,Chellappan, S.,Kairys, V.,Fernandes, M.X.,Gilson, M.K.,Schiffer, C.A.,Rana, T.M.,Tidor, B.
HIV-1 protease inhibitors from inverse design in the substrate envelope exhibit subnanomolar binding to drug-resistant variants.
J.Am.Chem.Soc., 130:6099-6113, 2008

PubMed Abstract: The acquisition of drug-resistant mutations by infectious pathogens remains a pressing health concern, and the development of strategies to combat this threat is a priority. Here we have applied a general strategy, inverse design using the substrate envelope, to develop inhibitors of HIV-1 protease. Structure-based computation was used to design inhibitors predicted to stay within a consensus substrate volume in the binding site. Two rounds of design, synthesis, experimental testing, and structural analysis were carried out, resulting in a total of 51 compounds. Improvements in design methodology led to a roughly 1000-fold affinity enhancement to a wild-type protease for the best binders, from a Ki of 30-50 nM in round one to below 100 pM in round two. Crystal structures of a subset of complexes revealed a binding mode similar to each design that respected the substrate envelope in nearly all cases. All four best binders from round one exhibited broad specificity against a clinically relevant panel of drug-resistant HIV-1 protease variants, losing no more than 6-13-fold affinity relative to wild type. Testing a subset of second-round compounds against the panel of resistant variants revealed three classes of inhibitors: robust binders (maximum affinity loss of 14-16-fold), moderate binders (35-80-fold), and susceptible binders (greater than 100-fold). Although for especially high-affinity inhibitors additional factors may also be important, overall, these results suggest that designing inhibitors using the substrate envelope may be a useful strategy in the development of therapeutics with low susceptibility to resistance.

PubMed: 18412349
DOI: 10.1021/ja076558p

Experimental method

X-RAY DIFFRACTION (1.95 Å)