Abstract
Consensus virtual screening models were generated and validated utilizing a set of known human epidermal growth factor receptor-2 (HER2) inhibitors and modeled HER2 active and inactive state structures. The virtual screening models were successfully employed to discover a set of structurally diverse compounds with growth inhibitory activity against HER2-overexpressing SKBR3 breast cancer cell line. A search of a 3D database containing 350000 small-molecules using the consensus models retrieved 531 potential hits. Of the 531 hits, 57 were selected for testing in SKBR3 cells on the basis of structural novelty and desirable drug-like properties. Seven compounds inhibited growth of SKBR3 cells with IC50 values <10 microM. These lead compounds have desirable physicochemical properties and are excellent candidates for further optimization.
Publication types
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Amino Acid Sequence
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Aniline Compounds / chemical synthesis
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Aniline Compounds / chemistry
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Aniline Compounds / pharmacology
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Antineoplastic Agents / chemical synthesis*
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology
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Binding Sites
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Breast Neoplasms
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Catalytic Domain
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Cell Line, Tumor
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Drug Screening Assays, Antitumor
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Female
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Heterocyclic Compounds, 2-Ring / chemical synthesis
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Heterocyclic Compounds, 2-Ring / chemistry
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Heterocyclic Compounds, 2-Ring / pharmacology
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Heterocyclic Compounds, 3-Ring / chemical synthesis
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Heterocyclic Compounds, 3-Ring / chemistry
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Heterocyclic Compounds, 3-Ring / pharmacology
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Humans
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Ligands
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Models, Molecular
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Molecular Sequence Data
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Piperazines / chemical synthesis
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Piperazines / chemistry
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Piperazines / pharmacology
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Pyrimidines / chemical synthesis
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Pyrimidines / chemistry
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Pyrimidines / pharmacology
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Quantitative Structure-Activity Relationship
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Quinazolines / chemical synthesis
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Quinazolines / chemistry
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Quinazolines / pharmacology
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Quinolines / chemical synthesis
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Quinolines / chemistry
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Quinolines / pharmacology
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Receptor, ErbB-2 / antagonists & inhibitors*
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Receptor, ErbB-2 / biosynthesis
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Small Molecule Libraries
Substances
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Aniline Compounds
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Antineoplastic Agents
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Heterocyclic Compounds, 2-Ring
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Heterocyclic Compounds, 3-Ring
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Ligands
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Piperazines
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Pyrimidines
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Quinazolines
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Quinolines
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Small Molecule Libraries
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Receptor, ErbB-2