Abstract:
:We have developed a coevolutionary method for the computational design of HIV-1 protease inhibitors selected for their ability to retain efficacy in the face of protease mutation. For HIV-1 protease, typical drug design techniques are shown to be ineffective for the design of resistance-evading inhibitors: An inhibitor that is a direct analogue of one of the natural substrates will be susceptible to resistance mutation, as will inhibitors designed to fill the active site of the wild-type or a mutant enzyme. Two design principles are demonstrated: (i) For enzymes with broad substrate specificity, such as HIV-1 protease, resistance-evading inhibitors are best designed against the immutable properties of the active site-the properties that must be conserved in any mutant protease to retain the ability to bind and cleave all of the native substrates. (ii) Robust resistance-evading inhibitors can be designed by optimizing activity simultaneously against a large set of mutant enzymes, incorporating as much of the mutational space as possible.
journal_name
Proc Natl Acad Sci U S Aauthors
Rosin CD,Belew RK,Morris GM,Olson AJ,Goodsell DSdoi
10.1073/pnas.96.4.1369subject
Has Abstractpub_date
1999-02-16 00:00:00pages
1369-74issue
4eissn
0027-8424issn
1091-6490journal_volume
96pub_type
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