Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Najran University, Najran 61441, Saudi Arabia.
Biomolecular Engineering Laboratory, School of Biochemical Engineering, Indian Institute of Technology, Banaras Hindu University, Varanasi 221005, India.
Molecules. 2021 Jan 22;26(3):582. doi: 10.3390/molecules26030582.
The Food and Drug Administration (FDA) approved a new class of anti-diabetic medication (a sodium-glucose co-transporter 2 (SGLT2) inhibitor) in 2013. However, SGLT2 inhibitor drugs are under evaluation due to their associative side effects, such as urinary tract and genital infection, urinary discomfort, diabetic ketosis, and kidney problems. Even clinicians have difficulty in recommending it to diabetic patients due to the increased probability of urinary tract infection. In our study, we selected natural SGLT2 inhibitors, namely acerogenin B, formononetin, (-)-kurarinone, (+)-pteryxin, and quinidine, to explore their potential against an emerging uropathogenic bacterial therapeutic target, i.e., FimH. FimH plays a critical role in the colonization of uropathogenic bacteria on the urinary tract surface. Thus, FimH antagonists show promising effects against uropathogenic bacterial strains via their targeting of FimH's adherence mechanism with less chance of resistance. The molecular docking results showed that, among natural SGLT2 inhibitors, formononetin, (+)-pteryxin, and quinidine have a strong interaction with FimH proteins, with binding energy (∆G) and inhibition constant (ki) values of -5.65 kcal/mol and 71.95 µM, -5.50 kcal/mol and 92.97 µM, and -5.70 kcal/mol and 66.40 µM, respectively. These interactions were better than those of the positive control heptyl α-d-mannopyranoside and far better than those of the SGLT2 inhibitor drug canagliflozin. Furthermore, a 50 ns molecular dynamics simulation was conducted to optimize the interaction, and the resulting complexes were found to be stable. Physicochemical property assessments predicted little toxicity and good drug-likeness properties for these three compounds. Therefore, formononetin, (+)-pteryxin, and quinidine can be proposed as promising SGLT2 inhibitors drugs, with add-on FimH inhibition potential that might reduce the probability of uropathogenic side effects.
美国食品和药物管理局（FDA）于 2013 年批准了一类新的抗糖尿病药物（钠-葡萄糖共转运蛋白 2（SGLT2）抑制剂）。然而，由于 SGLT2 抑制剂药物存在与尿路感染和生殖器感染、尿路不适、糖尿病酮症酸中毒和肾脏问题等相关的副作用，因此正在进行评估。即使是临床医生也因为尿路感染的概率增加而难以向糖尿病患者推荐这种药物。在我们的研究中，我们选择了天然的 SGLT2 抑制剂，即 Acerogenin B、芒柄花黄素、（-）苦参酮、（+）白屈菜红碱和奎尼丁，来探索它们对新兴的尿路致病性细菌治疗靶点 FimH 的潜在作用。FimH 在尿路致病性细菌在尿路表面的定植中起着关键作用。因此，FimH 拮抗剂通过靶向 FimH 的粘附机制，对尿路致病性菌株显示出有希望的效果，并且耐药的可能性较小。分子对接结果表明，在天然的 SGLT2 抑制剂中，芒柄花黄素、（+）白屈菜红碱和奎尼丁与 FimH 蛋白具有很强的相互作用，结合能（∆G）和抑制常数（ki）值分别为-5.65 kcal/mol 和 71.95 µM、-5.50 kcal/mol 和 92.97 µM、-5.70 kcal/mol 和 66.40 µM。这些相互作用优于阳性对照物庚基α-d-甘露吡喃糖苷，并且远优于 SGLT2 抑制剂药物坎格列净。此外，进行了 50 ns 的分子动力学模拟以优化相互作用，结果发现所得复合物是稳定的。物理化学性质评估预测这三种化合物毒性较小，具有良好的药物样性质。因此，芒柄花黄素、（+）白屈菜红碱和奎尼丁可以被提议为有前途的 SGLT2 抑制剂药物，具有附加的 FimH 抑制潜力，可能降低尿路致病性副作用的概率。
