London N

References (2)

Title : Overcoming insecticide resistance through computational inhibitor design - Correy_2019_Proc.Natl.Acad.Sci.U.S.A_116_21012
Author(s) : Correy GJ , Zaidman D , Harmelin A , Carvalho S , Mabbitt PD , Calaora V , James PJ , Kotze AC , Jackson CJ , London N
Ref : Proc Natl Acad Sci U S A , 116 :21012 , 2019
Abstract : Insecticides allow control of agricultural pests and disease vectors and are vital for global food security and health. The evolution of resistance to insecticides, such as organophosphates (OPs), is a serious and growing concern. OP resistance often involves sequestration or hydrolysis of OPs by carboxylesterases. Inhibiting carboxylesterases could, therefore, restore the effectiveness of OPs for which resistance has evolved. Here, we use covalent virtual screening to produce nano-/picomolar boronic acid inhibitors of the carboxylesterase alphaE7 from the agricultural pest Lucilia cuprina as well as a common Gly137Asp alphaE7 mutant that confers OP resistance. These inhibitors, with high selectivity against human acetylcholinesterase and low to no toxicity in human cells and in mice, act synergistically with the OPs diazinon and malathion to reduce the amount of OP required to kill L. cuprina by up to 16-fold and abolish resistance. The compounds exhibit broad utility in significantly potentiating another OP, chlorpyrifos, against the common pest, the peach-potato aphid (Myzus persicae). These compounds represent a solution to OP resistance as well as to environmental concerns regarding overuse of OPs, allowing significant reduction of use without compromising efficacy.
ESTHER : Correy_2019_Proc.Natl.Acad.Sci.U.S.A_116_21012
PubMedSearch : Correy_2019_Proc.Natl.Acad.Sci.U.S.A_116_21012
PubMedID: 31575743
Gene_locus related to this paper: luccu-E3aest7

Title : Covalent docking predicts substrates for haloalkanoate dehalogenase superfamily phosphatases - London_2015_Biochemistry_54_528
Author(s) : London N , Farelli JD , Brown SD , Liu C , Huang H , Korczynska M , Al-Obaidi NF , Babbitt PC , Almo SC , Allen KN , Shoichet BK
Ref : Biochemistry , 54 :528 , 2015
Abstract : Enzyme function prediction remains an important open problem. Though structure-based modeling, such as metabolite docking, can identify substrates of some enzymes, it is ill-suited to reactions that progress through a covalent intermediate. Here we investigated the ability of covalent docking to identify substrates that pass through such a covalent intermediate, focusing particularly on the haloalkanoate dehalogenase superfamily. In retrospective assessments, covalent docking recapitulated substrate binding modes of known cocrystal structures and identified experimental substrates from a set of putative phosphorylated metabolites. In comparison, noncovalent docking of high-energy intermediates yielded nonproductive poses. In prospective predictions against seven enzymes, a substrate was identified for five. For one of those cases, a covalent docking prediction, confirmed by empirical screening, and combined with genomic context analysis, suggested the identity of the enzyme that catalyzes the orphan phosphatase reaction in the riboflavin biosynthetic pathway of Bacteroides.
ESTHER : London_2015_Biochemistry_54_528
PubMedSearch : London_2015_Biochemistry_54_528
PubMedID: 25513739