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• W2819377575 startingPage "4934" @default.
• W2819377575 abstract "Human epidermal growth factor receptor 2 (HER2) is a validated breast cancer drug target for small molecule inhibitors that target the ATP-binding pocket of the kinase domain. In this work, a large-scale virtual screen was performed to a novel homology model of HER2, in a hypothesized “fully active” state, that considered water-mediated interactions during the prioritization of compounds for experimental testing. This screen led to the identification of a new inhibitor with micro molar affinity and potency (Kd = 7.0 μM, IC50 = 4.6 μM). Accompanying molecular dynamics simulations showed that inhibitor binding likely involves water coordination through an important water-mediated network previously identified in our laboratory. The predicted binding geometry also showed a remarkable overlap with the crystallographic poses for two previously reported inhibitors of the related Chk1 kinase. Concurrent with the HER2 studies, we developed formalized computational protocols that leverage solvated footprints (per-residue interaction maps that include bridging waters) to identify ligands that can “coordinate” or “displace” key binding site waters. Proof-of-concept screens targeting HIVPR and PARP1 demonstrate that molecules with high footprint overlap can be effectively identified in terms of their coordination or displacement patterns relative to a known reference. Overall, the procedures developed as a result of this study should be useful for researchers targeting HER2 and, more generally, for any protein in which the identification of compounds that exploit binding site waters is desirable." @default.
• W2819377575 created "2018-07-19" @default.
• W2819377575 creator A5015984763 @default.
• W2819377575 creator A5050315454 @default.
• W2819377575 creator A5052739866 @default.
• W2819377575 creator A5069720826 @default.
• W2819377575 date "2018-07-05" @default.
• W2819377575 modified "2023-10-09" @default.
• W2819377575 title "Identification of a Water-Coordinating HER2 Inhibitor by Virtual Screening Using Similarity-Based Scoring" @default.
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• W2819377575 doi "https://doi.org/10.1021/acs.biochem.8b00524" @default.
• W2819377575 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/6110523" @default.
• W2819377575 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/29975516" @default.
• W2819377575 hasPublicationYear "2018" @default.
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