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bioRxiv · 10.64898/2026.06.16.732538

From hotspot dependence to distributed robustness in resistance-aware lead optimization

Wang, Y.·Xiao, B.·Kang, J.·Cui, H.·Fu, Y.·Li, W.·Perea, S. E.·Han, W.
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Abstract

Drug resistance remains a recurrent failure mode in targeted anticancer and antiviral therapy, and resistance evidence often enters only after compound selection. ResistAgent is an evidence-constrained framework that converts mutational liabilities into design-time objectives through site- and combo-aware resistance mapping, deterministic mechanism diagnosis and robust counter-design. In EGFR-Erlotinib and HIV-RT-Rilpivirine, the framework separated residue-level liabilities from observed HIV combination liabilities and linked prioritized mutations to anchor loss, pocket rearrangement, electrostatic shifts and contact redistribution. Same-budget paired searches showed that robust objectives changed lower-tail mutant-panel behavior and interaction-dependence profiles while prioritizing robustness over average-affinity behavior. Under predefined liability panels, robust-objective trajectories shifted support away from mutable hotspot contacts toward more distributed interaction networks. Supplementary physical summaries and ranking-first benchmarks support the validation envelope of this resistance-aware design strategy.

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Wang, Y., Xiao, B., Kang, J., Cui, H., Fu, Y., Li, W., Perea, S. E., Han, W.. 2026-06-22. From hotspot dependence to distributed robustness in resistance-aware lead optimization. https://doi.org/10.64898/2026.06.16.732538

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