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Matched Analogue Analysis of Structural Responses Before and After Covalent Bond Formation in Wild-Type and A775_G776insYVMA HER2

Year: 2026

Type: article

Abstract: Endpoint structure–activity relationships (SAR) 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 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 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 but reduced it in the 9c/11f series. 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. No single structural readout tracked endpoint potency across all six pairs. These analyses complement experimental SAR but do not provide a measure of reaction kinetics or thermodynamic populations.

Source: International Journal of Molecular Sciences

DOI: 10.3390/ijms27209057