2qi4: Difference between revisions

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[[Image:2qi4.jpg|left|200px]]
{{Seed}}
[[Image:2qi4.png|left|200px]]


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{{STRUCTURE_2qi4|  PDB=2qi4  |  SCENE=  }}  
{{STRUCTURE_2qi4|  PDB=2qi4  |  SCENE=  }}  


'''Crystal structure of protease inhibitor, MIT-2-AD93 in complex with wild type HIV-1 protease'''
===Crystal structure of protease inhibitor, MIT-2-AD93 in complex with wild type HIV-1 protease===




==Overview==
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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.
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{{ABSTRACT_PUBMED_18412349}}


==About this Structure==
==About this Structure==
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[[Category: Hydrolase]]
[[Category: Hydrolase]]
[[Category: Protease inhibitor]]
[[Category: Protease inhibitor]]
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu May 22 22:28:29 2008''
 
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Jul 28 21:39:29 2008''

Revision as of 18:39, 28 July 2008

File:2qi4.png

Template:STRUCTURE 2qi4

Crystal structure of protease inhibitor, MIT-2-AD93 in complex with wild type HIV-1 protease

Template:ABSTRACT PUBMED 18412349

About this Structure

2QI4 is a Single protein structure of sequence from Human immunodeficiency virus 1. Full crystallographic information is available from OCA.

Reference

HIV-1 protease inhibitors from inverse design in the substrate envelope exhibit subnanomolar binding to drug-resistant variants., Altman MD, Ali A, Reddy GS, Nalam MN, Anjum SG, Cao H, Chellappan S, Kairys V, Fernandes MX, Gilson MK, Schiffer CA, Rana TM, Tidor B, J Am Chem Soc. 2008 May 14;130(19):6099-113. Epub 2008 Apr 16. PMID:18412349

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