Identification of a Water-Coordinating HER2 Inhibitor by Virtual Screening Using Similarity-Based Scoring.

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 ( K_d = 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 showe

SUBMITTER: Guo J 

PROVIDER: S-EPMC6110523 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature