DNA旋转酶
DNA
化学
生物化学
拓扑异构酶
DNA超螺旋
虚拟筛选
结核分枝杆菌
拓扑异构酶
立体化学
生物
作者
Bongkochawan Pakamwong,Paptawan Thongdee,Bundit Kamsri,Naruedon Phusi,Pharit Kamsri,Auradee Punkvang,Sombat Ketrat,Patchreenart Saparpakorn,Supa Hannongbua,Kanchiyaphat Ariyachaokun,Khomson Suttisintong,Sanya Sureram,Prasat Kittakoop,Poonpilas Hongmanee,Pitak Santanirand,James Spencer,J. L. Ross Anderson,Pornpan Pungpo
标识
DOI:10.1021/acs.jcim.1c01390
摘要
Mycobacterium tuberculosis DNA gyrase manipulates the DNA topology using controlled breakage and religation of DNA driven by ATP hydrolysis. DNA gyrase has been validated as the enzyme target of fluoroquinolones (FQs), second-line antibiotics used for the treatment of multidrug-resistant tuberculosis. Mutations around the DNA gyrase DNA-binding site result in the emergence of FQ resistance in M. tuberculosis; inhibition of DNA gyrase ATPase activity is one strategy to overcome this. Here, virtual screening, subsequently validated by biological assays, was applied to select candidate inhibitors of the M. tuberculosis DNA gyrase ATPase activity from the Specs compound library (www.specs.net). Thirty compounds were identified and selected as hits for in vitro biological assays, of which two compounds, G24 and G26, inhibited the growth of M. tuberculosis H37Rv with a minimal inhibitory concentration of 12.5 μg/mL. The two compounds inhibited DNA gyrase ATPase activity with IC50 values of 2.69 and 2.46 μM, respectively, suggesting this to be the likely basis of their antitubercular activity. Models of complexes of compounds G24 and G26 bound to the M. tuberculosis DNA gyrase ATP-binding site, generated by molecular dynamics simulations followed by pharmacophore mapping analysis, showed hydrophobic interactions of inhibitor hydrophobic headgroups and electrostatic and hydrogen bond interactions of the polar tails, which are likely to be important for their inhibition. Decreasing compound lipophilicity by increasing the polarity of these tails then presents a likely route to improving the solubility and activity. Thus, compounds G24 and G26 provide attractive starting templates for the optimization of antitubercular agents that act by targeting DNA gyrase.
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