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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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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