Matched Analogue Analysis of Structural Responses Before and After Covalent Bond Formation in Wild-Type and A775_G776insYVMA HER2
- 1Beijing Key Laboratory of Environmental and Viral Oncology, College of Chemistry and Life Science, Beijing University of Technology, Beijing 100124, China
- 2Beijing Key Laboratory for Green Catalysis and Separation, Beijing University of Technology, Beijing 100124, China
- 3Beijing Academy of Artificial Intelligence (BAAI), Beijing 100080, China
Abstract
Endpoint structure–activity relationships (SARs) for irreversible inhibitors can integrate reversible binding, covalent chemistry, conformational behavior, and cellular factors, making it difficult to assign a potency change to a single molecular event. We reanalyzed a previously reported series of irreversible inhibitors of wild-type (WT) HER2 and HER2 A775_G776insYVMA (HER2YVMA) as six matched analogue pairs. Three complementary analyses were kept physically distinct. Pre-reaction molecular dynamics (MD) trajectories were used to quantify the fraction of frames satisfying a predefined near-attack-conformation (NAC)-like distance–angle criterion; continuous structural descriptors calculated from OpenComplex2 (OC2)-generated covalently linked HER2–inhibitor structures were used to characterize structural differences after covalent linkage; and covalent-adduct MD trajectories were used to characterize post-bond-formation dynamics. The Michael addition step itself was neither simulated nor measured. Cyclization of compound 3 to compound 9c increased the NAC-like frame fraction in HER2WT from 0.0217% to 0.358% but decreased it in HER2YVMA from 0.745% to 0.333%, with the overall direction preserved across all six sensitivity definitions. In HER2YVMA, the modification distinguishing compounds 4a and 5a increased the NAC-like fraction from 2.620% to 6.244% despite a loss of cellular potency. The analogous tail modification increased this fraction in the 8c/10e series, whereas the HER2YVMA 9c/11f response was starting conformation sensitive. The distribution of OC2-generated covalently linked structures across the predefined structural coordinate and the final-adduct MD readouts likewise varied with HER2 context and scaffold, although some differential effects were sensitive to the coordinate reference. These analyses complement experimental SARs but do not provide a measure of reaction kinetics or thermodynamic populations.
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BibTeX
@article{fan2026matched,
title = {{Matched Analogue Analysis of Structural Responses Before and After Covalent Bond Formation in Wild-Type and A775_G776insYVMA HER2}},
author = {Keke Fan and Yanan Xu and Qiwei Ye and Mingliang Zeng and Hongwang Xiao and Shanyan Mo and Sha Hu and Liming Hu},
journal = {International Journal of Molecular Sciences},
year = {2026},
month = oct,
doi = {10.3390/ijms27209057},
url = {https://www.mdpi.com/1422-0067/27/20/9057},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Matched Analogue Analysis of Structural Responses Before and After Covalent Bond Formation in Wild-Type and A775_G776insYVMA HER2
AU - Keke Fan
AU - Yanan Xu
AU - Qiwei Ye
AU - Mingliang Zeng
AU - Hongwang Xiao
AU - Shanyan Mo
AU - Sha Hu
AU - Liming Hu
PY - 2026
DA - 2026/10/01
JO - International Journal of Molecular Sciences
DO - 10.3390/ijms27209057
UR - https://www.mdpi.com/1422-0067/27/20/9057
AB - Endpoint structure–activity relationships (SARs) for irreversible inhibitors can integrate reversible binding, covalent chemistry, conformational behavior, and cellular factors, making it difficult to assign a potency change to a single molecular event. We reanalyzed a previously reported series of irreversible inhibitors of wild-type (WT) HER2 and HER2 A775_G776insYVMA (HER2YVMA) as six matched analogue pairs. Three complementary analyses were kept physically distinct. Pre-reaction molecular dynamics (MD) trajectories were used to quantify the fraction of frames satisfying a predefined near-attack-conformation (NAC)-like distance–angle criterion; continuous structural descriptors calculated from OpenComplex2 (OC2)-generated covalently linked HER2–inhibitor structures were used to characterize structural differences after covalent linkage; and covalent-adduct MD trajectories were used to characterize post-bond-formation dynamics. The Michael addition step itself was neither simulated nor measured. Cyclization of compound 3 to compound 9c increased the NAC-like frame fraction in HER2WT from 0.0217% to 0.358% but decreased it in HER2YVMA from 0.745% to 0.333%, with the overall direction preserved across all six sensitivity definitions. In HER2YVMA, the modification distinguishing compounds 4a and 5a increased the NAC-like fraction from 2.620% to 6.244% despite a loss of cellular potency. The analogous tail modification increased this fraction in the 8c/10e series, whereas the HER2YVMA 9c/11f response was starting conformation sensitive. The distribution of OC2-generated covalently linked structures across the predefined structural coordinate and the final-adduct MD readouts likewise varied with HER2 context and scaffold, although some differential effects were sensitive to the coordinate reference. These analyses complement experimental SARs but do not provide a measure of reaction kinetics or thermodynamic populations.
SN - 1422-0067
ER -