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

UMMS Affiliation

Department of Biochemistry and Molecular Pharmacology

Publication Date


Document Type



Chitinase; Computer Simulation; *Drug Design; Drug Resistance, Viral; Enzyme Inhibitors; HIV Protease; Humans; Mutation; Neuraminidase; Protein Binding; Proto-Oncogene Proteins c-abl; Software; Tetrahydrofolate Dehydrogenase; Thymidylate Synthase


Biochemistry, Biophysics, and Structural Biology | Pharmacology, Toxicology and Environmental Health


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 that the substrate envelope concept offers a promising and easily implemented computational tool for the design of drugs that will tend to resist mutations. Software implementing these calculations is provided with the 'Supporting Information'.

DOI of Published Version



Chem Biol Drug Des. 2009 Sep;74(3):234-45. Link to article on publisher's site

Journal/Book/Conference Title

Chemical biology and drug design

Related Resources

Link to Article in PubMed

PubMed ID