A metal-aware library-expansion and virtual-screening workflow for Pseudomonas aeruginosa ATCC 15692 (PAO1) MraY identifies compound 5311309 with stable binding and mid-micromolar activity
Year: 2026
Type: article
Abstract: Introduction Pseudomonas aeruginosa lung infections are difficult to eradicate because of biofilms and rising resistance. MraY (MRAY_PSEAE), an essential membrane enzyme in peptidoglycan biosynthesis, depends on divalent metals (notably Mg 2+ ); therefore, metal coordination is critical for reliable structure-based prioritization. Methods We built an explicit protein–ligand–metal model of MRAY_PSEAE and extracted pocket constraints from point-cloud geometry and polar/charged features. Candidates were generated through similarity-guided library expansion, combining PubChem 2D similarity retrieval with local rule-based BRICS enumeration. After canonicalization and 2D/property filtering, compounds were clustered by fingerprint similarity and prioritized through chemical-state plausibility, docking, Prime/MM-GBSA rescoring, and ligand strain filtering, followed by interaction analysis, 1-μs MD, and in silico ADMET. Results Three hits (6675, 2733768, 5311309) were prioritized. In microsecond MD, compound 5311309 showed the most stable pose and key hotspot retention. ADMET indicated a permeability/efflux bottleneck along with liver–kidney and irritation/sensitization alerts, whereas hERG and AMES signals were favorable. In growth assays, compound 5311309 showed an IC50 of approximately 15.1 μM and an MIC of 64 μM. Conclusion Metal-aware pocket modeling plus multi-level screening improved plausibility and ranking for this metal-dependent target, identifying compound 5311309 as a practical lead optimization starting point.
Source: Frontiers in Microbiology
Language: English
Subfield: Computational Theory and Mathematics
Field: Computer Science
Domain: Physical Sciences
Open Access status: gold
Estimated APC paid: $3,801
OpenAlex ID: W7151329602