| Autor: |
Mashraqi MM; Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Najran University, Najran 61441, Saudi Arabia., Chaturvedi N; Biomolecular Engineering Laboratory, School of Biochemical Engineering, Indian Institute of Technology, Banaras Hindu University, Varanasi 221005, India.; Department of Molecular and Cell Biology, Leicester Institute of Structural and Chemical Biology, University of Leicester Henry Wellcome Building, Lancaster Road Leicester, Leicester LE1 7HB, UK., Alam Q; Medical Genomics Research Department, King Abdullah International Medical Research Center (KAIMRC), King Saud Bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City, Ministry of National Guard Health Affairs, Riyadh 11426, Saudi Arabia., Alshamrani S; Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Najran University, Najran 61441, Saudi Arabia., Bahnass MM; Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Najran University, Najran 61441, Saudi Arabia.; Department of Animal Medicine (Infectious Diseases), Faculty of Veterinary Medicine, Zagazig University, Zagazig 44519, Egypt., Ahmad K; Department of Medical Biotechnology, Yeungnam University, Gyeongsan 38541, Korea., Alqosaibi AI; Department of Biology, College of Science, Imam Abdulrahman bin Faisal University, P.O. Box 1982, Dammam 31441, Saudi Arabia., Alnamshan MM; Department of Biology, College of Science, Imam Abdulrahman bin Faisal University, P.O. Box 1982, Dammam 31441, Saudi Arabia., Ahmad SS; Department of Medical Biotechnology, Yeungnam University, Gyeongsan 38541, Korea., Beg MMA; Department of Medical Biotechnology, Yeungnam University, Gyeongsan 38541, Korea., Mishra A; Biomolecular Engineering Laboratory, School of Biochemical Engineering, Indian Institute of Technology, Banaras Hindu University, Varanasi 221005, India., Shaikh S; Department of Medical Biotechnology, Yeungnam University, Gyeongsan 38541, Korea., Rizvi SMD; Department of Pharmaceutics, College of Pharmacy, University of Hail, P.O. Box 2440, Hail 81451, Saudi Arabia. |
| Abstrakt: |
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. |
