Coevolutionary analysis of resistance-evading peptidomimetic inhibitors of HIV-1 protease.

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.

authors

Rosin CD,Belew RK,Morris GM,Olson AJ,Goodsell DS

doi

10.1073/pnas.96.4.1369

subject

Has Abstract

pub_date

1999-02-16 00:00:00

pages

1369-74

issue

4

eissn

0027-8424

issn

1091-6490

journal_volume

96

pub_type

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