Molecular Dynamics-Guided Triage of Approved Drugs Against Escherichia coli Resistance Targets Nominates Capmatinib, Metergoline and Nilotinib as Candidates for Experimental Testing

Virtual screening ranks compounds by scoring functions that correlate with molecular size, and hit lists are rarely benchmarked against compounds of established activity. We screened 2070 approved drugs against four Escherichia coli targets selected by pocket-druggability triage (FabI, LpxC, DHFR and GyrB), with each docking protocol validated by redocking its native ligand (RMSD 0.50–0.69 Å). Per target, the two top-scoring compounds and a reference inhibitor were simulated for 100 ns in triplicate (12 complexes, 3.6 µs). Docking did not recover the references: trimethoprim ranked 762/2068 and novobiocin 576/2069, while top-ranked compounds were large, promiscuous drugs recurring across unrelated targets. Pose triage failed, too: all twelve complexes retained 43–87% of initial contacts, contact-loss time separated targets, not compounds, and MM-GBSA favoured the reference at one target of four. Persistent hydrogen bonding separated the reference from the hits at three of four targets, by 2–9-fold, although the GyrB result rests largely on one replicate. Benchmarking each hit against its reference nominates three candidates for experimental testing: capmatinib at DHFR, metergoline at FabI and nilotinib at LpxC. Capmatinib ranks highest on these computational criteria, with the highest pocket retention (87%) and an MM-GBSA energy with no detectable difference from trimethoprim’s at n = 3 (absence of evidence for a difference, not evidence of equivalence). In this small panel, carrying a known active through the same pipeline was therefore more informative than docking score, pose stability or end-point rescoring. The nominations are hypotheses: no experimental validation was performed, and generality would require multiple actives and property-matched decoys per target.

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