Testing the substrate-envelope hypothesis with designed pairs of compounds
Authors
Shen, YangAltman, Michael D.
Ali, Akbar
Nalam, Madhavi N. L.
Cao, Hong
Rana, Tariq M.
Schiffer, Celia A.
Tidor, Bruce
UMass Chan Affiliations
Chemical Biology ProgramDepartment of Biochemistry and Molecular Pharmacology
Document Type
Journal ArticlePublication Date
2013-11-15Keywords
BiochemistryBiochemistry, Biophysics, and Structural Biology
Chemistry
Medicinal Chemistry and Pharmaceutics
Molecular Biology
Pharmacology
Metadata
Show full item recordAbstract
Acquired resistance to therapeutic agents is a significant barrier to the development of clinically effective treatments for diseases in which evolution occurs on clinical time scales, frequently arising from target mutations. We previously reported a general strategy to design effective inhibitors for rapidly mutating enzyme targets, which we demonstrated for HIV-1 protease inhibition [Altman et al. J. Am. Chem. Soc. 2008, 130, 6099-6113]. Specifically, we developed a computational inverse design procedure with the added constraint that designed inhibitors bind entirely inside the substrate envelope, a consensus volume occupied by natural substrates. The rationale for the substrate-envelope constraint is that it prevents designed inhibitors from making interactions beyond those required by substrates and thus limits the availability of mutations tolerated by substrates but not by designed inhibitors. The strategy resulted in subnanomolar inhibitors that bind robustly across a clinically derived panel of drug-resistant variants. To further test the substrate-envelope hypothesis, here we have designed, synthesized, and assayed derivatives of our original compounds that are larger and extend outside the substrate envelope. Our designs resulted in pairs of compounds that are very similar to one another, but one respects and one violates the substrate envelope. The envelope-respecting inhibitor demonstrates robust binding across a panel of drug-resistant protease variants, whereas the envelope-violating one binds tightly to wild type but loses affinity to at least one variant. This study provides strong support for the substrate-envelope hypothesis as a design strategy for inhibitors that reduce susceptibility to resistance mutations.Source
ACS Chem Biol. 2013 Nov 15;8(11):2433-41. doi: 10.1021/cb400468c. Epub 2013 Sep 26. Link to article on publisher's siteDOI
10.1021/cb400468cPermanent Link to this Item
http://hdl.handle.net/20.500.14038/26073PubMed ID
23952265Related Resources
Link to Article in PubMedae974a485f413a2113503eed53cd6c53
10.1021/cb400468c