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Identification of previously unrecognized antiestrogenic chemicals using a novel virtual screening approach.

ABSTRACT: The physiological roles of estrogen in sexual differentiation and development, female and male reproductive processes, and bone health are complex and diverse. Numerous natural and synthetic chemical compounds, commonly known as endocrine disrupting chemicals (EDCs), have been shown to alter the physiological effects of estrogen in humans and wildlife. As such, these EDCs may cause unanticipated and even undesirable effects. Large-scale in vitro and in vivo screening of chemicals to assess their estrogenic activity would demand a prodigious investment of time, labor, and money and would require animal testing on an unprecedented scale. Approaches in silico are increasingly recognized as playing a vital role in screening and prioritizing chemicals to extend limited resources available for experimental testing. Here, we evaluated a multistep procedure that is suitable for in silico (virtual) screening of large chemical databases to identify compounds exhibiting estrogenic activity. This procedure incorporates Shape Signatures, a novel computational tool that rapidly compares molecules on the basis of similarity in shape, polarity, and other bio-relevant properties. Using 4-hydroxy tamoxifen (4-OH TAM) and diethylstilbestrol (DES) as input queries, we employed this scheme to search a sample database of approximately 200,000 commercially available organic chemicals for matches (hits). Of the eight compounds identified computationally as potentially (anti)estrogenic, biological evaluation confirmed two as heretofore unknown estrogen antagonists. Subsequent radioligand binding assays confirmed that two of these three compounds exhibit antiestrogenic activities comparable to 4-OH TAM. Molecular modeling studies of these ligands docked inside the binding pocket of estrogen receptor alpha (ERalpha) elucidated key ligand-receptor interactions that corroborate these experimental findings. The present study demonstrates the utility of our computational scheme for this and related applications in drug discovery, predictive toxicology, and virtual screening.

SUBMITTER: Wang CY

PROVIDER: S-EPMC2705242 | biostudies-literature | 2006 Dec

REPOSITORIES: biostudies-literature

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Identification of previously unrecognized antiestrogenic chemicals using a novel virtual screening approach.

Wang Ching Y CY Ai Ni N Arora Sonia S Erenrich Eric E Nagarajan Karthigeyan K Zauhar Randy R Young Douglas D Welsh William J WJ

Chemical research in toxicology 20061201 12

The physiological roles of estrogen in sexual differentiation and development, female and male reproductive processes, and bone health are complex and diverse. Numerous natural and synthetic chemical compounds, commonly known as endocrine disrupting chemicals (EDCs), have been shown to alter the physiological effects of estrogen in humans and wildlife. As such, these EDCs may cause unanticipated and even undesirable effects. Large-scale in vitro and in vivo screening of chemicals to assess their ...[more]

PMID: 17173372

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Project description:P2X4 and P2X7 receptors are ATP-gated ion channels, which play important roles in neuropathic and inflammatory pain, and as such they are important drug targets in diseases of inflammatory origin. While several compounds targeting P2X4 and P2X7 receptors have been developed using traditional high-throughput screening approaches, relatively few compounds have been developed using structure-based design. We initially set out to develop compounds targeting human P2X4, by performing virtual screening on the orthosteric (ATP-binding) pocket of a molecular model of human P2X4 based on the crystal structure of the Danio rerio receptor. The screening of a library of approximately 300,000 commercially available drug-like compounds led to the initial selection of 17 compounds; however, none of these compounds displayed a significant antagonist effect at P2X4 in a Fluo-4 ATP-induced calcium influx assay. When the same set of compounds was tested against human P2X7 in an ATP-stimulated Yo-Pro1 dye uptake assay, one compound (an indeno(1,2-b)pyridine derivative; GP-25) reduced the response by greater than 50% when applied at a concentration of 30 µM. GP-25 displayed an IC50 value of 8.7 μM at human P2X7 and 24.4 μM at rat P2X7, and was confirmed to be active using whole-cell patch clamp electrophysiology and not cytotoxic. Schild analysis suggested that mode of action of GP-25 was orthosteric. Screening of a further 16 commercially available analogues of GP-25 led to the discovery of five additional compounds with antagonist activity at human P2X7, enabling us to investigate the structure-activity relationship. Finally, docking of the R- and S-enantiomers of GP-25 into the orthosteric pocket of molecular models of human P2X4 and human P2X7 revealed that, while both enantiomers were able to make multiple interactions between their carboxyl moieties and conserved positively charged amino-acids in human P2X7, only the S-enantiomer of GP-25 was able to do this in human P2X4, potentially explaining the lack of activity of GP-25 at this receptor.

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Identification of previously unrecognized antiestrogenic chemicals using a novel virtual screening approach.

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Identification of previously unrecognized antiestrogenic chemicals using a novel virtual screening approach.

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