Toward the design of mutation-resistant enzyme inhibitors: further evaluation of the substrate envelope hypothesis.

ABSTRACT: 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 therapeutic targets: Abl kinase, chitinase, thymidylate synthase, dihydrofolate reductase, and neuraminidase. For the targets where many (> or =6) mutation data are available to compute the average mutation sensitivity of inhibitors, the total volume of an inhibitor molecule that projects outside the substrate envelope V(out), is found to correlate with average mutation sensitivity. Analysis of a locally computed volume suggests that the same correlation would hold for the other targets, if more extensive mutation data sets were available. It is concluded

SUBMITTER: Kairys V 

PROVIDER: S-EPMC2860775 | biostudies-literature | 2009 Sep

REPOSITORIES: biostudies-literature