基于分子对接筛选肺炎克雷伯菌β-内酰胺金属酶NDM-1抑制剂及活性研究OA

Objective To screen potential inhibitors based on the three-dimensional structure of NDM-1 enzyme and evaluate their pharmacological activity.Methods Computer-aided drug design methods were employed to screen the top 5 candidate compounds with the highest molecular docking scores from the 50K Diversity Library.The minimum inhibitory concentration(MIC)was further determined in combination with meropenem,imipenem,and ceftazidime to assess their inhibitory activity against NDM-1.The stability of the candidate compounds binding to NDM-1 was analyzed through molecular dynamics simulation.Results When the top 5 compounds with the highest molecular docking scores were combined with three β-lactam antibiotics,the MIC values showed no significant reduction,suggesting limited inhibitory effects on NDM-1.Molecular dynamics simulation revealed that compounds 1,3,4,and 5 exhibited large root-mean-square deviation(RMSD)and free energy fluctuations in the reaction system,indicating unstable conformations;although compound 2 showed no significant RMSD fluctuation,its binding free energy value was relatively low,potentially resulting in insufficient binding affinity.Conclusion Differences in binding stability between the five candidate compounds and NDM-1 protein led to their overall limited inhibitory activity.