Disrupting Survival Pathways: CHEMBL35-derived Inhibitors Targeting Transcription-repair Coupling Factor in Acinetobacter baumannii LAC-4

Acinetobacter baumannii is a coccobacillus, a gram-negative pathogenic bacterium, that can be an opportunistic pathogen affecting immunocompromised patients. A. baumannii is becoming an increasingly important causative agent of hospital-associated infections and poses an important threat to worldwide health, emphasizing the necessity for discovering new therapeutic agents to tackle this global health concern. This research work is designed to identify novel inhibitors against the transcription-repair coupling factor for therapeutic applications of A. baumannii using computer-aided drug design (CADD). Docking analysis calculated − 10, -7.7, and − 7.1 binding affinity scores for CHEMBL3938673 (Top-1), CHEMBL3959129 Top-2 and CHEMBL3662388 (Top-3) compounds. The docked molecules were further investigated through molecular (MD) simulations analysis using Assisted model building with energy refinement (AMBER-22 packages). Overall, the simulation trajectories revealed that the docked molecules remain stable during a 150-nanosecond (ns) time frame. Moreover, the (MD) simulation and molecular docking findings were further validated using MMGBSA and MMPBSA analysis. In MMGBSA binding energy estimation, -68.22, -73.28, and − 53.66 net energy (kcal/mol) were calculated for Top-1, Top-2, and Top-3 docked molecules, respectively. The MMPBSA analysis calculated − 65.63, -74.77, and − 52.27 net energy (kcal/mol) for Top-1, Top-2, and Top-3 docked complexes, respectively. The negative binding free energies calculated through MM-GBSA and MMPBSA analysis validated the thermodynamic stability and strong stability ability of the ligand protein complexes, supporting their prospects as promising drug candidates for therapeutic application. The SwissADME tool predicted that the selected lead compound from molecular docking exhibits moderate solubility (Log S: -4.98 and − 5.12), moderate-to-high lipophilicity (consensus Log P: 3.75), high GI absorption, and blood-brain barrier permeability, while sustaining Lipinski’s Rule of Five with a bioavailability score of 0.55. Overall, all the computational investigations revealed that the selected compounds have proper binding affinity with the target transcription-repair coupling factor A. baumannii LAC-4; however, experimental validations are required to confirm the computational findings.