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 (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.

Identification of Fatty Acid Binding Protein 5 Inhibitors Through Similarity-Based Screening

“…23 The FLX protocol samples ligand torsion and rigid body degrees of freedom using the anchor and grow algorithm with the receptor (FABP5) being held rigid. We have previously employed this DOCK procedure to successfully identify inhibitors targeting HIVgp41, 34−37 FABP, 12,19 HER2, 38 and BoNT. 39,40 For each screened molecule, only the best grid-based energy conformation (pose) was retained.…”

“…We have employed similar MD protocols (i.e., overall setup, equilibration and production procedures, simulation lengths) to characterize protein–ligand binding in a variety of systems. 35−38,40…”

Free Energy Landscapes for RBD Opening in SARS-CoV-2 Spike Glycoprotein Simulations Suggest Key Interactions and a Potentially Druggable Allosteric Pocket

“…We carried out virtual screening using DOCK6, 59 with a setup that followed well-tested protocols we previously employed to identify small molecule inhibitors through targeting HIV gp41, [60][61][62] fatty acid binding proteins, [63][64] botulinum neurotoxins, [65][66] HER2, 67 Ebola GP2, 68 Zika glycoprotein E 69 . We screened libraries of purchasable molecules downloadable from the ZINC database 70 .…”

Ligand‐based Discovery of Novel Small Molecule Inhibitors of RON Receptor Tyrosine Kinase

“…A large number of virtual screening studies have been reported for identification of TKIs against different RTKs [22–25] . However, in the case of RON receptor tyrosine kinase, there is no report for such computational studies.…”

“…[20][21] A large number of virtual screening studies have been reported for identification of TKIs against different RTKs. [22][23][24][25] However, in the case of RON receptor tyrosine kinase, there is no report for such computational studies. Considering the importance of RON as a promising target in cancer therapy, in the current study we aimed to identify new lead RON inhibitors using ligand-based virtual screening.…”