title: 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 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'.
authors.affiliation: Centro de Química da Madeira, Departamento de Química, Universidade da Madeira, 9000-390 Funchal, Portugal.
authors.forename: Visvaldas
authors.initials: V
authors.lastname: Kairys
authors.forename: Michael K
authors.initials: MK
authors.lastname: Gilson
authors.forename: Viney
authors.initials: V
authors.lastname: Lather
authors.forename: Celia A
authors.initials: CA
authors.lastname: Schiffer
authors.forename: Miguel X
authors.initials: MX
authors.lastname: Fernandes
mesh_terms: D002688:Chitinases / Q000378:metabolism; D003198:Computer Simulation; D015195:Drug Design; D024882:Drug Resistance, Viral; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D016333:HIV Protease / Q000378:metabolism; D006801:Humans; D009154:Mutation; D009439:Neuraminidase / Q000378:metabolism; D011485:Protein Binding; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism; D012984:Software; D013762:Tetrahydrofolate Dehydrogenase / Q000378:metabolism; D013940:Thymidylate Synthase / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D013762:Tetrahydrofolate Dehydrogenase; D013940:Thymidylate Synthase; D016315:Proto-Oncogene Proteins c-abl; D002688:Chitinases; D009439:Neuraminidase; D016333:HIV Protease
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