| Structural highlights
2qhy is a 2 chain structure with sequence from 9hiv1. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | , , |
| Related: | 2qhz, 2qi0, 2qi1, 2qi3, 2qi4, 2qi5, 2qi6, 2qi7 |
| Gene: | pol (9HIV1) |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum |
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
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.
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[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ 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. HIV-1 protease inhibitors from inverse design in the substrate envelope exhibit subnanomolar binding to drug-resistant variants. J Am Chem Soc. 2008 May 14;130(19):6099-113. Epub 2008 Apr 16. PMID:18412349 doi:10.1021/ja076558p
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