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In Silico Design and Evaluation of Carboxylesterase Inhibitors.

ABSTRACT: Carboxylesterases (CEs) are important enzymes that catalyze biological detoxification, hydrolysis of certain pesticides, and metabolism of many esterified drugs. The development of inhibitors for CE has many potential uses, including increasing drug lifetime and altering biodistrubution; reducing or abrogating toxicity of metabolized drugs; and reducing pest resistance to insecticides. In this review, we discuss the major classes of known mammalian CE inhibitors and describe our computational efforts to design new scaffolds for development of novel, selective inhibitors. We discuss several strategies for in silico inhibitor development, including structure docking, database searching, multidimensional quantitative structure activity analysis (QSAR), and a newly-used approach that uses QSAR combined with de novo drug design. While our research is focused on design of specific inhibitors for human intestinal carboxylesterase (hiCE), the methods described are generally applicable to inhibitors of other enzymes, including CE from other tissues and organisms.

SUBMITTER: Stoddard SV

PROVIDER: S-EPMC3593733 | biostudies-literature | 2010

REPOSITORIES: biostudies-literature

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In Silico Design and Evaluation of Carboxylesterase Inhibitors.

Stoddard Shana V SV Yu Xiaozhen X Potter Philip M PM Wadkins Randy M RM

Journal of pest science 20100101 3

Carboxylesterases (CEs) are important enzymes that catalyze biological detoxification, hydrolysis of certain pesticides, and metabolism of many esterified drugs. The development of inhibitors for CE has many potential uses, including increasing drug lifetime and altering biodistrubution; reducing or abrogating toxicity of metabolized drugs; and reducing pest resistance to insecticides. In this review, we discuss the major classes of known mammalian CE inhibitors and describe our computational ef ...[more]

PMID: 23487487

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Project description:IntroductionEpidermal growth factor receptor (EGFR) inhibition is an imperative therapeutic approach targeting various types of cancer including colorectal, lung, breast, and pancreatic cancer types. Moreover, cyclooxygenase-2 (COX-2) is frequently overexpressed in different types of cancers and has a role in the promotion of malignancy, apoptosis inhibition, and metastasis of tumor cells. Combination therapy has been emerged to improve the therapeutic benefit against cancer and curb intrinsic and acquired resistance.MethodsThree semi-synthetic series of compounds (C1-4, P1-4, and G1-4) were prepared and evaluated biologically as potential dual epidermal growth factor receptor (EGFR) and COX-2 inhibitors. The main phenolic constituents of Amaranthus spinosus L. (p-coumaric, caffeic and gallic) acids have been isolated and subsequently subjected to diazo coupling with various amines to get novel three chemical scaffolds with potential anticancer activities.ResultsCompounds C4 and G4 showed superior inhibitory activity against EGFR (IC50: 0.9 and 0.5 µM, respectively) and displayed good COX-2 inhibition (IC50: 4.35 and 2.47 µM, respectively). Moreover, the final compounds were further evaluated for their cytotoxic activity against human colon cancer (HT-29), pancreatic cancer (PaCa-2), human malignant melanoma (A375), lung cancer (H-460), and pancreatic ductal cancer (Panc-1) cell lines. Interestingly, compounds C4 and G4 exhibited the highest cytotoxic activity with average IC50 values of 1.5 µM and 2.8 µM against H-460 and Panc-1, respectively. The virtual docking study was conducted to gain proper understandings of the plausible-binding modes of target compounds within EGFR and COX-2 binding sites.DiscussionThe NMR of prepared compounds showed characteristic peaks that confirmed the structure of the target compounds. The synthesized benzoxazolyl scaffold containing compounds showed inhibitory activities for both COXs and EGFR which are consistent with the virtual docking study.

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In Silico Design and Evaluation of Carboxylesterase Inhibitors.

Publications

In Silico Design and Evaluation of Carboxylesterase Inhibitors.

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