Identification of novel natural MurD ligase inhibitors as potential antimicrobial agents targeting Acinetobacter baumannii: In silico screening and biological evaluation

• Published in: Journal of biomolecular structure & dynamics 2022-01, Vol.40 (24), p.14051-14066
• Main Authors: Tiwari, Pragya, Sharma, Priyanka, Kumar, Mukesh, Kapil, Arti, Abdul Samath, Ethayathulla, Kaur, Punit
• Format: Article
• Language: English
• Subjects: Acinetobacter baumannii - metabolism; Anti-Bacterial Agents - chemistry; Ligases - metabolism; MIC assay; MMPBSA energy; Molecular docking; Molecular Docking Simulation; Molecular Dynamics Simulation; MurD; Virtual screening
• ISSN: 0739-1102; 1538-0254
• DOI: 10.1080/07391102.2021.2000497

The increased multidrug resistance in Acinetobacter baumannii (A. baumannii) to the present-day known antibiotics has stimulated academic and industrial efforts globally for the development of novel antibacterial agents. Natural compounds as potential drug leads are gaining significant attention due to their less toxic and more tolerant nature. In the current study, the natural product-based compounds were explored as probable inhibitors of UDP-N-acetylmuramoyl-L-alanine:D-glutamate (MurD) ligase from A.baumannii (AbMurD) to provide a new class of drug leads. The prepared natural library of 3,16,714 compounds from ZINC database was screened into the active site of AbMurD using in silico high-throughput virtual screening which resulted in 100 compounds having high binding affinities. Further screening through flexible molecular docking yielded four potential compounds selected on the basis of estimated binding affinity (ΔG) and favorable protein-ligand interactions. MD simulation of these four compounds under physiological conditions and free binding energy calculations using MM/PBSA (molecular mechanics with Poisson- Boltzmann and surface area solvation) approach revealed three compounds ZINC08879777, ZINC30726863, and ZINC95486217 as potential binders of AbMurD. The calculated physicochemical and ADME properties of these compounds revealed that they can be exploited and modified to improve their binding affinity with the enzyme. Two compounds were purchased and tested against bacterial cell cultures of A. baumannii, Salmonella Typhi, and Staphylococcus aureus to determine their broad-spectrum antibacterial activity. The results suggest that the identified compounds can be exploited as potential herbal leads to target both Gram-positive and Gram-negative pathogens. Communicated by Ramaswamy H. Sarma