Structure-based identification of a membrane-retained OmpA candidate against Acinetobacter baumannii by membrane molecular dynamics and phenotypic antibacterial assessment

Outer membrane protein A (OmpA) contributes to the envelope integrity and virulence of Acinetobacter baumannii and contains a lumenal cavity that may accommodate small molecules. We screened 99,878 ChEMBL-derived compounds against a structural model of the OmpA transmembrane barrel using two rounds of docking followed by short aqueous molecular-dynamics triage. Two scaffold-diverse compounds were then examined in 500-ns simulations of OmpA embedded in a POPE:POPG membrane. CHEMBL3394804 (Hit 1) remained within the lumen through persistent interactions with Lys120 and Arg160, whereas CHEMBL1075891 (Hit 2) was retained for approximately 275 ns and then lost sustained pocket contact. Umbrella-sampling free-energy profiles independently supported stronger retention of Hit 1. An authenticated sample of Hit 1 inhibited growth of the antibiotic-susceptible reference strain A. baumannii ATCC 19606 at 32 micrograms per millilitre, reduced biofilm formation, and caused concentration-dependent protein leakage and loss of metabolic viability. These cellular effects are consistent with outer-membrane perturbation but do not by themselves establish direct OmpA engagement, and they do not exclude oxidative stress or another non-specific mechanism of envelope damage. Together, the results identify Hit 1 as a membrane-retained computational OmpA candidate with antibacterial activity in a drug-susceptible reference strain. Direct target-engagement studies and evaluation in resistant clinical strains are required to establish mechanism and broader antibacterial relevance.