Browsing by Author "Schiffer, Celia A."
Now showing 1 - 3 of 3
Results Per Page
Sort Options
- Design of mutation-resistant HIV protease inhibitors with the substrate envelope hypothesisPublication . Chellappan, Sripriya; Kiran Kumar Reddy, G. S.; Ali, Akbar; Nalam, Madhavi N. L.; Anjum, Saima Ghafoor; Cao, Hong; Kairys, Visvaldas; Fernandes, Miguel X.; Altman, Michael D.; Tidor, Bruce; Rana, Tariq M.; Schiffer, Celia A.; Gilson, Michael K.There is a clinical need for HIV protease inhibitors that can evade resistance mutations. One possible approach to designing such inhibitors relies upon the crystallographic observation that the sub strates of HIV protease occupy a rather constant region within the binding site. In particular, it has been hypothesized that inhibitors which lie within this region will tend to resist clinically relevant mutations. The present study offers the first pros pective evaluation of this hypothesis, via compu tational design of inhibitors predicted to conform to the substrate envelope, followed by synthesis and evaluation against wild-type and mutant pro teases, as well as structural studies of complexes of the designed inhibitors with HIV protease. The results support the utility of the substrate envel ope hypothesis as a guide to the design of robust protease inhibitors.
- HIV-1 protease inhibitors from inverse design in the substrate envelope exhibit subnanomolar binding to drug-resistant variantsPublication . Altman, Michael D.; Ali, Akbar; Kumar Reddy, G. S. Kiran; Nalam, Madhavi N. L.; Anjum, Saima Ghafoor; Cao, Hong; Chellappan, Sripriya; Kairys, Visvaldas; Fernandes, Miguel X.; Gilson, Michael K.; Schiffer, Celia A.; Rana, Tariq M.; Tidor, BruceThe 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.
- Toward the design of mutation‐resistant enzyme inhibitors: further evaluation of the substrate envelope hypothesisPublication . Kairys, Visvaldas; Gilson, Michael K.; Lather, Viney; Schiffer, Celia A.; Fernandes, Miguel X.Previous studies have shown the usefulness of the substrate envelope concept in the analysis and prediction of drug resistance profiles for human immunodeficiency virus protease mutants. This study tests its applicability to several other thera peutic targets: Abl kinase, chitinase, thymidylate synthase, dihydrofolate reductase, and neuramini dase. For the targets where many (‡6) mutation data are available to compute the average mutation sen sitivity of inhibitors, the total volume of an inhibitor molecule that projects outside the substrate enve lope Vout, is found to correlate with average muta tion sensitivity. Analysis of a locally computed volume suggests that the same correlation would hold for the other targets, if more extensive muta tion data sets were available. It is concluded that the substrate envelope concept offers a promising and easily implemented computational tool for the design of drugs that will tend to resist muta tions. Software implementing these calculations is provided with the ’Supporting Information’.