Toward the design of mutation-resistant enzyme inhibitors: further evaluation of the substrate envelope hypothesis.
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'.
Kairys
Visvaldas
V
Centro de Química da Madeira, Departamento de Química, Universidade da Madeira, 9000-390 Funchal, Portugal.
Gilson
Michael K
MK
Lather
Viney
V
Schiffer
Celia A
CA
Fernandes
Miguel X
MX
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
D004791:Enzyme Inhibitors; D013762:Tetrahydrofolate Dehydrogenase; D013940:Thymidylate Synthase; D016315:Proto-Oncogene Proteins c-abl; D002688:Chitinases; D009439:Neuraminidase; D016333:HIV Protease
N Engl J Med. 2005 Sep 29;353(13):1363-73
16192481
Nat Rev Cancer. 2005 Mar;5(3):172-83
15719031
Biochem Pharmacol. 2006 Mar 30;71(7):941-8
16359642
Nucleic Acids Res. 2000 Jan 1;28(1):235-42
10592235
BMJ. 2005 Nov 26;331(7527):1219-20
16308360
Drug Discov Today. 2005 Jan 15;10(2):121-8
15718161
Structure. 1998 Jun 15;6(6):735-46
9655825
Chem Biol. 2004 Oct;11(10):1333-8
15489160
Chem Biol. 2005 Jan;12(1):65-76
15664516
PLoS Biol. 2006 May;4(5):e144
16640460
Proteins. 2007 Aug 1;68(2):561-7
17474129
Vaccine. 2002 May 15;20 Suppl 2:S55-8
12110259
Chem Biol. 2007 May;14(5):589-99
17524989
J Clin Invest. 2007 Sep;117(9):2562-9
17710227
Prog Biophys Mol Biol. 2005 Jun;88(2):193-208
15572155
J Pathol. 2005 Jan;205(2):275-92
15641020
Nat Med. 2007 Mar;13(3):295-8
17342143
Biochemistry. 1989 Dec 26;28(26):9881-90
2695162
J Mol Graph. 1996 Feb;14(1):33-8, 27-8
8744570
Curr Med Chem. 2005;12(19):2241-58
16178783
J Am Chem Soc. 2008 May 14;130(19):6099-113
18412349
Proc Natl Acad Sci U S A. 2001 Jul 31;98(16):8979-84
11481469
J Med Virol. 2007 Oct;79(10):1577-86
17705169
J Phys Chem B. 1998 Apr 30;102(18):3586-616
24889800
Semin Hematol. 2007 Jan;44(1 Suppl 1):S15-24
17292737
Proc Natl Acad Sci U S A. 2002 Jul 9;99(14):9127-32
12093900
Curr Pharm Des. 2003;9(31):2593-613
14529544
Protein Eng. 2000 Aug;13(8):535-43
10964982
Expert Rev Anti Infect Ther. 2005 Apr;3(2):191-9
15918777
Chem Biol Drug Des. 2007 May;69(5):298-313
17539822
Nucleic Acids Res. 2007 Jan;35(Database issue):D198-201
17145705