Quantum Reactivity-Guided Optimization of ATP-Competitive Ligands through Multiscale Simulation
Source: PubMed Central Open Access, NCBI / U.S. National Library of Medicine
ATP-binding pockets impose stringent geometric and electronic constraints on small-molecule ligands, requiring preservation of key anchoring interactions while permitting only limited scaffold modification. Rational optimization of ATP-competitive inhibitors therefore remains challenging, particularly when electronic reactivity and metabolic liability must be balanced against binding stability. We explored a multiscale, quantum-informed computational strategy to address this challenge using the receptor tyrosine kinase-like orphan receptor 1 (ROR1) pseudokinase domain, an underexplored intracellular cancer target that retains a druggable ATP-binding pocket, as a chemically informative model system. Using Ponatinib as an internal reference scaffold, eight Fukui-guided analogs () were designed through density functional theory analyses integrating Mulliken, Löwdin and Hirshfeld charge partitioning with Fukui function mapping. These calculations identified electronically reactive and metabolically labile regions amenable to site-specific modification at,,, and, while preserving the alkyne and carbonyl motifs responsible for anchoring interactions within the ATP-binding pocket. To establish a robust energetic and dynamical baseline, 1 μs all-atom molecular dynamics simulations were performed for the ROR1 pseudokinase domain in both apo and Ponatinib-bound states. The designed analogs were subsequently evaluated using 250 ns simulations combined with relative MM-PBSA binding free-
Abstract
ATP-binding pockets impose stringent geometric and electronic constraints on small-molecule ligands, requiring preservation of key anchoring interactions while permitting only limited scaffold modification. Rational optimization of ATP-competitive inhibitors therefore remains challenging, particularly when electronic reactivity and metabolic liability must be balanced against binding stability. We explored a multiscale, quantum-informed computational strategy to address this challenge using the receptor tyrosine kinase-like orphan receptor 1 (ROR1) pseudokinase domain, an underexplored intracellular cancer target that retains a druggable ATP-binding pocket, as a chemically informative model system. Using Ponatinib as an internal reference scaffold, eight Fukui-guided analogs () were designed through density functional theory analyses integrating Mulliken, Löwdin and Hirshfeld charge partitioning with Fukui function mapping. These calculations identified electronically reactive and metabolically labile regions amenable to site-specific modification at,,, and, while preserving the alkyne and carbonyl motifs responsible for anchoring interactions within the ATP-binding pocket. To establish a robust energetic and dynamical baseline, 1 μs all-atom molecular dynamics simulations were performed for the ROR1 pseudokinase domain in both apo and Ponatinib-bound states. The designed analogs were subsequently evaluated using 250 ns simulations combined with relative MM-PBSA binding free-energy analysis, revealing a narrow binding-energy range (Δ_bind ≈ −37 to −45 kcal mol) comparable to Ponatinib (−41.78 ± 5.65 kcal molat 250 ns; −40.23 ± 5.61 kcal molat 1 μs). Interaction fingerprint analysis confirmed conservation of the hinge-anchored--network and the-aromatic clamp across the series. In silico ADME profiling differentiated developability among energetically similar compounds, identifying–as the most balanced analogs. Collectively, quantum-mechanical reactivity descriptors can delineate electronically feasible scaffold modification sites within ATP-binding pocketspositions where chemical perturbation is tolerated without disrupting anchoring pharmacophore interactionsproviding substantively complementary information distinct from, classical energy-based scoring or empirical SAR. http://www.w3.org/1999/xlink float portrait pg6c00012_0018.jpg graphical http://www.w3.org/1999/xlink tgr1 not-for-print float portrait pg6c00012_0016.jpg toc-graphic