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Discovery of novel fibroblast growth factor receptor 1 kinase inhibitors by structure-based virtual screening.

ABSTRACT: Fibroblast growth factors (FGFs) play important roles in embryonic development, angiogenesis, wound healing, and cell proliferation and differentiation. In search of inhibitors of FGFR1 kinase, 2.2 million compounds were docked into the ATP binding site of the protein. A co-crystal structure, which shows two alternative conformations for the nucleotide binding loop, is reported. Docking was performed on both conformations and, ultimately, 23 diverse compounds were purchased and assayed. Following hit validation, two compounds 10 and 16, a benzylidene derivative of pseudothiohydantoin and a thienopyrimidinone derivative, respectively, were discovered that inhibit FGFR1 kinase with IC(50) values of 23 and 50 microM. Initial optimization of 16 led to the more unsaturated 40, which has significantly enhanced potency, 1.9 microM. The core structures represent new structural motifs for FGFR1 kinase inhibitors. The study also illustrates complexities associated with the choice of protein structures for docking, possible use of multiple kinase structures to seek selectivity, and hit identification.

SUBMITTER: Ravindranathan KP

PROVIDER: S-EPMC2842983 | biostudies-literature | 2010 Feb

REPOSITORIES: biostudies-literature

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Discovery of novel fibroblast growth factor receptor 1 kinase inhibitors by structure-based virtual screening.

Ravindranathan Krishna P KP Mandiyan Valsan V Ekkati Anil R AR Bae Jae H JH Schlessinger Joseph J Jorgensen William L WL

Journal of medicinal chemistry 20100201 4

Fibroblast growth factors (FGFs) play important roles in embryonic development, angiogenesis, wound healing, and cell proliferation and differentiation. In search of inhibitors of FGFR1 kinase, 2.2 million compounds were docked into the ATP binding site of the protein. A co-crystal structure, which shows two alternative conformations for the nucleotide binding loop, is reported. Docking was performed on both conformations and, ultimately, 23 diverse compounds were purchased and assayed. Followin ...[more]

PMID: 20121196

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Project description:BackgroundHuman epidermal growth factor receptor-2 (HER2) is a trans-membrane receptor like protein, and aberrant signaling of HER2 is implicated in many human cancers, such as ovarian cancer, gastric cancer, and prostate cancer, most notably breast cancer. Moreover, it has been in the spotlight in the recent years as a promising new target for therapy of breast cancer.ObjectiveSince virtual screening has become an integral part of the drug discovery process, it is of great significant to identify novel HER2 inhibitors by structure-based virtual screening.Materials and methodsIn this study, we carried out a series of elegant bioinformatics approaches, such as virtual screening and molecular dynamics (MD) simulations to identify HER2 inhibitors from Food and Drug Administration-approved small molecule drug as potential "new use" drugs.ResultsMolecular docking identified top 10 potential drugs which showed spectrum affinity to HER2. Moreover, MD simulations suggested that ZINC08214629 (Nonoxynol-9) and ZINC03830276 (Benzonatate) might exert potential inhibitory effects against HER2-targeted anti-breast cancer therapeutics.ConclusionTogether, our findings may provide successful application of virtual screening studies in the lead discovery process, and suggest that our discovered small molecules could be effective HER2 inhibitor candidates for further study.SummaryA series of elegant bioinformatics approaches, including virtual screening and molecular dynamics (MD) simulations were took advantage to identify human epidermal growth factor receptor-2 (HER2) inhibitors. Molecular docking recognized top 10 candidate compounds, which showed spectrum affinity to HER2. Further, MD simulations suggested that ZINC08214629 (Nonoxynol-9) and ZINC03830276 (Benzonatate) in candidate compounds were identified as potential "new use" drugs against HER2-targeted anti-breast cancer therapeutics. Abbreviations used: HER2: Human epidermal growth factor receptor-2, FDA: Food and Drug Administration, PDB: Protein Database Bank, RMSDs: Root mean square deviations, SPC: Single point charge, PME: Particle mesh Ewald, NVT: Constant volume, NPT: Constant pressure, RMSF: Root-mean-square fluctuation.

Dataset Information

Discovery of novel fibroblast growth factor receptor 1 kinase inhibitors by structure-based virtual screening.

Publications

Discovery of novel fibroblast growth factor receptor 1 kinase inhibitors by structure-based virtual screening.

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