Identification of Potent and Selective CYP1A1 Inhibitors via Combined Ligand and Structure-Based Virtual Screening and Their in Vitro Validation in Sacchrosomes and Live Human Cells.

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dc.cclicenceN/Aen
dc.contributor.authorJoshi, Prashanten
dc.contributor.authorMcCann, Glen J. P.en
dc.contributor.authorSonawane, V. R.en
dc.contributor.authorVishwakarma, R. A.en
dc.contributor.authorChaudhuri, B.en
dc.contributor.authorBharate, S. B.en
dc.date.acceptance2017-06-26en
dc.date.accessioned2018-11-02T11:11:58Z
dc.date.available2018-11-02T11:11:58Z
dc.date.issued2017-05-10
dc.descriptionGuidance, training & key materials provided by Dr Neill Horleyen
dc.description.abstractTarget structure-guided virtual screening (VS) is a versatile, powerful, and inexpensive alternative to experimental high-throughput screening (HTS). To discover potent CYP1A1 enzyme inhibitors for cancer chemoprevention, a commercial library of 50 000 small molecules was utilized for VS guided by both ligand and structure-based strategies. For experimental validation, 300 ligands were proposed based on combined analysis of fitness scores from ligand based e-pharmacophore screening and docking score, prime MMGB/SA binding affinity and interaction pattern analysis from structure-based VS. These 300 compounds were screened, at 10 μM concentration, for in vitro inhibition of CYP1A1-Sacchrosomes (yeast-derived microsomal enzyme) in the ethoxyresorufin-O-de-ethylase assay. Thirty-two compounds displayed >50% inhibition of CYP1A1 enzyme activity at 10 μM. 2-Phenylimidazo-[1,2-a]quinoline (5121780, 119) was found to be the most potent with 97% inhibition. It also inhibited ∼95% activity of CYP1B1 and CYP1A2, the other two CYP1 enzymes. The compound 5121780 (119) showed high selectivity toward inhibition of CYP1 enzymes with respect to CYP2 and CYP3 enzymes (i.e., there was no detectable inhibition of CYP2D6/CYP2C9/CYP2C19 and CYP3A4 at 10 μM). It was further investigated in live CYP-expressing human cell system, which confirmed that compound 5121780 (119) potently inhibited CYP1A1, CYP1A2, CYP1B1 enzymes with IC50 values of 269, 30, and 56 nM, respectively. Like in Sacchrosomes, inhibition of CYP2D6/CYP2C9/CYP2C19 and CYP3A4 enzymes, expressed within live human cells, could hardly be detected at 10 μM. The compound 119 rescued CYP1A1 overexpressing HEK293 cells from CYP1A1 mediated benzo[a]pyrene (B[a]P) toxicity and also overcame cisplatin resistance in CYP1B1 overexpressing HEK293 cells. Molecular dynamics simulations of 5121780 (119) with CYP1 enzymes was performed to understand the interaction pattern to CYP isoforms. Results indicate that VS can successfully be used to identify promising CYP1A1 inhibitors, which may have potential in the development of novel cancer chemo-preventive agents.en
dc.exception.reasonFull text not deposited within 3 months of acceptanceen
dc.explorer.multimediaNoen
dc.funderN/Aen
dc.identifier.citationJoshi, P., McCann, G.J.P., Sonawane, V.R., Vishwakarma, R.A., Chaudhuri, B., Bharate, S.B. (2017) Identification of Potent and Selective CYP1A1 Inhibitors via Combined Ligand and Structure-Based Virtual Screening and Their in Vitro Validation in Sacchrosomes and Live Human Cells. Journal of Chemical Information and Modeling, 57, pp. 1309–1320en
dc.identifier.doihttps://doi.org/10.1021/acs.jcim.7b00095
dc.identifier.urihttp://hdl.handle.net/2086/17038
dc.language.isoenen
dc.peerreviewedYesen
dc.projectidN/Aen
dc.publisherACS Publicationsen
dc.researchinstituteLeicester Institute for Pharmaceutical Innovation - From Molecules to Practice (LIPI)en
dc.subjectP450en
dc.subjectCYP1A1en
dc.subjectinhibitorsen
dc.subjectVirtual Screeningen
dc.titleIdentification of Potent and Selective CYP1A1 Inhibitors via Combined Ligand and Structure-Based Virtual Screening and Their in Vitro Validation in Sacchrosomes and Live Human Cells.en
dc.typeArticleen

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