title: 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.affiliation: Department of Computer Science and Engineering, University of California at San Diego, La Jolla, CA 92093, USA.
authors.forename: C D
authors.initials: CD
authors.lastname: Rosin
authors.forename: R K
authors.initials: RK
authors.lastname: Belew
authors.forename: G M
authors.initials: GM
authors.lastname: Morris
authors.forename: A J
authors.initials: AJ
authors.lastname: Olson
authors.forename: D S
authors.initials: DS
authors.lastname: Goodsell
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D015195:Drug Design; D019143:Evolution, Molecular; D016333:HIV Protease / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D015497:HIV-1 / Q000201:enzymology / Q000235:genetics; D007700:Kinetics; D017354:Point Mutation; D013816:Thermodynamics