Biocomputational Prediction Approach Targeting FimH by Natural SGLT2 Inhibitors: A Possible Way to Overcome the Uropathogenic Effect of SGLT2 Inhibitor Drugs

Abstract

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.

D-Mannoside FimH Inhibitors as Non-Antibiotic Alternatives for Uropathogenic Escherichia coli

“…These interactions remained in relative equilibrium during the dynamics and as a consequence are more likely to also interact when tested in vivo. The stability of the receptor–ligand complex is measured by conformational changes in the dynamic behavior of the complex [ 41 , 42 , 43 ]. RMSD values can vary throughout the stabilization process of the complex, which contributes to identifying the interaction or binding coupling between FimH proteins and binders [ 44 ].…”

Five-Decade Update on Chemopreventive and Other Pharmacological Potential of Kurarinone: a Natural Flavanone

“…It has been postulated that the natural compound possessing the inhibitory action against both targets may be used as potential anti-diabetic agents having kisser side effects. In the study kurarinone showed potential binding (−7 kcal/mole) against an SGLT transporter but moderate binding (about −4 kcal/mole) with the FimH protein ( Mashraqi et al, 2021 ).…”

“…The bacteria used to attach with the host cells by Type 1 pili (which possess FimH protein). Mashraqi et al (2021) studied the human SGLT transporter and bacterial FimH protein inhibition potential of natural flavonoids using computer aided drug discovery approach. It has been postulated that the natural compound possessing the inhibitory action against both targets may be used as potential anti-diabetic agents having kisser side effects.…”

Phytochemicals as Regulators of Tumor Glycolysis and Hypoxia Signaling Pathways: Evidence from In Vitro Studies

“…Interestingly, phloretin, the hydrolysis product of phlorizin, demonstrated GLUT-inhibitory properties [ 64 ]. So far, several natural compounds have been identified as potential SLGT1 or SLGT2 inhibitors in various structure-based simulated scanning studies: (−)-kurarinone and sophoraflavanone G isolated from Sophora flavescens roots [ 65 ], gneyulins A and B isolated from the bark of Gnetum gnemonoides [ 66 ], farnesal and farnesol acyclic terpenoids extracted from Annona diversifolia Safford leaves [ 67 ], phlorizin, (+)-pteryxin, (+)-ε-viniferin [ 68 ], formononetin, and (+)-pteryxin [ 69 ]. However, these compounds have been evaluated only as potential antidiabetic agents, and, therefore, supplementary cytotoxicity studies are needed to assess their role in tumor glycolysis and their anticancer potential.…”