金属酶活性位点对比法发现新的金属β-内酰胺酶抑制剂  

Discovery of new metallo-β-lactamase inhibitors with the metalloenzyme active site comparison method

作　　者：李根 朱开容 郭丽[1] LI Gen;ZHU Kairong;GUO Li(West China School of Pharmacy,Sichuan University,Chengdu,Sichuan,610041 P.R.China)

机构地区：[1]四川大学华西药学院,四川成都610041

出　　处：《华西药学杂志》2021年第5期501-504,共4页West China Journal of Pharmaceutical Sciences

基　　金：国家自然科学基金资助项目(批准号:81874291)。

摘　　要：目的采用金属酶活性位点对比法,发现新的金属β-内酰胺酶(MBL)抑制剂。方法用自主发展的金属酶活性位点对比法,将MBL活性位点与其他金属酶的活性位点进行对比,从与其相似活性位点所结合的配体中提炼出可能与MBL结合的金属结合药效团骨架,其中,双膦酸骨架具备良好的发展潜力;再用分子对接预测双膦酸骨架与MBL亚型VIM-2的相互作用模式,最后从上市药物中遴选双膦酸类化合物并进行活性验证。结果利塞膦酸钠、阿伦膦酸钠、米诺膦酸和唑来膦酸等4种药物均对VIM-2亚型表现出了中等强度的抑制活性,其中,阿伦膦酸钠的活性最好,IC50值为25.08μmol·L^(-1)。结论金属酶活性位点对比方法可为靶向MBL药物研发提供了新的苗头/先导化合物。OBJECTIVE To discover novel metallo-β-lactamase(MBL) inhibitors based on the metalloenzyme active site comparison.METHODS Firstly, the active sites of MBL were compared with those of other metalloenzymes by the metalloenzyme active site comparison method that constructed in-house.The metal-bound pharmacophore skeletons were extracted from the ligands bound to the active sites similar to MBL,among which the bisphosphonic acid skeleton had a good development potential.Then, molecular docking was used to predict the interaction pattern between the bisphosphonic acid skeleton and the MBL subtype VIM-2.Finally, the bisphosphonates were selected from the approved drugs and their activities were verified.RESULTS Sodium Risedronate, sodium Alendronate, Minodronate and Zoledronic acid all showed moderate inhibitory activity against the VIM-2 subtype of MBL,among which sodium Alendronate showed the best inhibitory activity with IC50 value of 25.08 μmol·L^(-1).CONCLUSION Metalloenzyme active site comparison method can be provided precursor/lead compounds for drug development of targeting MBL.

关 键 词：金属酶 活性位点对比 金属结合药效团 分子对接 金属Β-内酰胺酶 双膦酸 筛选 药物重定位 药物发现 苗头/先导化合物 

分 类 号：R914[医药卫生—药物化学]