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Overcoming insecticide resistance through computational inhibitor design.

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 ?E7 from the agricultural pest Lucilia cuprina as well as a common Gly137Asp ?E7 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.

SUBMITTER: Correy GJ

PROVIDER: S-EPMC6800356 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Overcoming insecticide resistance through computational inhibitor design.

Correy Galen J GJ Zaidman Daniel D Harmelin Alon A Carvalho Silvia S Mabbitt Peter D PD Calaora Viviane V James Peter J PJ Kotze Andrew C AC Jackson Colin J CJ London Nir N

Proceedings of the National Academy of Sciences of the United States of America 20191001 42

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 bo ...[more]

PMID: 31575743

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Project description:Rationale: The Polycomb group (PcG) protein EZH2 is implicated in cancer progression due to its frequent overexpression in many cancer types and therefore is a promising therapeutic target. Forkhead box transcription factor-1 (FOXO1) is a tumor suppressor that is often transcriptionally downregulated in human cancers such as prostate cancer although the underlying regulatory mechanisms remain elusive. Methods: Analysis of EZH2 ChIP-seq and ChIP-on-chip data in various cell types was performed. ChIP-qPCR, RT-qPCR, and western blot analyses were conducted to determine the mechanism by which EZH2 represses FOXO1 expression. Immunohistochemistry was employed to assess the correlation between EZH2 and FOXO1 protein expression in prostate cancer patient specimens. In vitro MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) and animal experiments were performed to determine the anti-cancer efficacy of EZH2 inhibitor alone or in combination of docetaxel, a chemotherapy agent of the taxane family, and dependency of the efficacy on FOXO1 expression. Results: We demonstrated that EZH2 binds to the FOXO1 gene promoter. EZH2 represses FOXO1 gene expression at the transcriptional level. EZH2 protein level inversely correlated with FOXO1 protein expression in prostate cancer patient specimens. This repression requires the methyltransferase activity and the functional PRC2 complex. While effectively inducing loss of viability of PTEN-positive 22Rv1 prostate cancer cells, EZH2 inhibitor failed to inhibit growth of PTEN-negative C4-2 prostate cancer cells. Co-treatment with docetaxel overcame EZH2 inhibitor resistance in PTEN-negative cancer cells in vitro and in mice. This effect was largely mediated by docetaxel-induced nuclear localization and activation of FOXO1. Conclusions: This study identifies FOXO1 as a bona fide repression target of EZH2 and an essential mediator of EZH2 inhibition-induced cell death. Our findings suggest that EZH2 repression of FOXO1 can be targeted by EZH2 inhibitor as a monotherapy for PTEN-proficient cancers or in combination with taxane for treatment of cancers with PTEN mutation or deletion.

Project description:Background In 2003, the first case of severe acute respiratory syndrome coronavirus (SARS-CoV) was recorded. Coronaviruses (CoVs) have caused a major outbreak of human fatal pneumonia. Currently, there is no specific drug or treatment for diseases caused by SARS CoV 2. Computational approach that adopts dynamic models is widely accepted as indispensable tool in drug design but yet to be exploited in covid-19 in Zaria, Nigeria. In this study, steps were taken to advance on the successful achievements in the field of covid-19 drug, with the aid of in silico drug design technique, to create novel inhibitor drug candidates with better activity. In this study, one thousand human immunodeficiency virus (HIV1) antiviral chemical compounds from www.bindingBD.org were docked on the SARS CoV 2 main protease protein data bank identification number 6XBH (PDB ID: 6XBH) and the molecular docking score were ranked in order to identify the compounds with the highest inhibitory effects, and easy selection for future studies. Results The docking studies showed some interesting results. Inhibitors with Index numbers 331, 741, and 819 had the highest binding affinity. Similarly, inhibitors with Index number 441, 847, and 46 had the lowest hydrogen bond energy. Inhibitor with index number 331 was reported with the lowest value (− 48.38kCal/mol). Five new compounds were designed from the selected six (6) compounds with the best binding score giving a total of thirty (30) novel compounds. The low binding energy of inhibitor with index no. 847b is unique, as most of the interaction energies are of H-bond type with amino acids (Thr26, Gly143, Ser144, Cys145, Glu166, Gln189, Hie164, Met49, Thr26, Thr25, Thr190, Asn142, Met165) resulting in an overall negative value (−16.31 kCal/mol) making it the best of all the newly designed inhibitors. Conclusions The novel inhibitor is 2-(2-(5-amino-2-((((3-aminobenzyl)oxy)carbonyl)amino)-5-oxopentanamido)-4-(2-(tert-butyl)-4-oxo-4-(pentan-3-ylamino) butanamido)-3-hydroxybutyl) benzoic acid. The improvement it has over the parent inhibitor is from the primary amine group attached to meta position of first benzene ring and the carboxyl group attached to the ortho position of the second benzene ring. The molecular dynamics studies also show that the novel inhibitor remains stable after the study. This result makes it a better drug candidate against SARS CoV 2 main protease when compared with the co-crystallized inhibitor or any of the 1000 docked inhibitors. Supplementary Information The online version contains supplementary material available at 10.1186/s42269-022-00892-z.

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Overcoming insecticide resistance through computational inhibitor design.

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Overcoming insecticide resistance through computational inhibitor design.

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