Exploring potent aldose reductase inhibitors for anti-diabetic (anti-hyperglycemic) therapy: integrating structure-based drug design, and MMGBSA approaches
Aldose reductase (AR) is an important target in the development of therapeutics against hyper-glycemia-induced health complications such as retinopathy, etc. In this study, we employed a combination of structure-based drug design, molecular simulation, and free energy calculation approaches to ident...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-11-01
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| Series: | Frontiers in Molecular Biosciences |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fmolb.2023.1271569/full |
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| author | Muhammad Shahab Guojun Zheng Fahad M. Alshabrmi Mohammed Bourhia Gezahign Fentahun Wondmie Ahmad Mohammad Salamatullah |
| author_facet | Muhammad Shahab Guojun Zheng Fahad M. Alshabrmi Mohammed Bourhia Gezahign Fentahun Wondmie Ahmad Mohammad Salamatullah |
| author_sort | Muhammad Shahab |
| collection | DOAJ |
| description | Aldose reductase (AR) is an important target in the development of therapeutics against hyper-glycemia-induced health complications such as retinopathy, etc. In this study, we employed a combination of structure-based drug design, molecular simulation, and free energy calculation approaches to identify potential hit molecules against anti-diabetic (anti-hyperglycemic)-induced health complications. The 3D structure of aldoreductase was screened for multiple compound libraries (1,00,000 compounds) and identified as ZINC35671852, ZINC78774792 from the ZINC database, Diamino-di nitro-methyl dioctyl phthalate, and Penta-o-galloyl-glucose from the South African natural compounds database, and Bisindolylmethane thiosemi-carbazides and Bisindolylme-thane-hydrazone from the Inhouse database for this study. The mode of binding interactions of the selected compounds later predicted their aldose reductase inhibitory potential. These com-pounds interact with the key active site residues through hydrogen bonds, salt bridges, and π-π interactions. The structural dynamics and binding free energy results further revealed that these compounds possess stable dynamics with excellent binding free energy scores. The structures of the lead inhibitors can serve as templates for developing novel inhibitors, and in vitro testing to confirm their anti-diabetic potential is warranted. The current study is the first to design small molecule inhibitors for the aldoreductase protein that can be used in the development of therapeutic agents to treat diabetes. |
| first_indexed | 2024-03-10T18:48:43Z |
| format | Article |
| id | doaj.art-c20980c19c984d3d9348658e0571d959 |
| institution | Directory Open Access Journal |
| issn | 2296-889X |
| language | English |
| last_indexed | 2024-03-10T18:48:43Z |
| publishDate | 2023-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Molecular Biosciences |
| spelling | doaj.art-c20980c19c984d3d9348658e0571d9592023-11-20T05:22:11ZengFrontiers Media S.A.Frontiers in Molecular Biosciences2296-889X2023-11-011010.3389/fmolb.2023.12715691271569Exploring potent aldose reductase inhibitors for anti-diabetic (anti-hyperglycemic) therapy: integrating structure-based drug design, and MMGBSA approachesMuhammad Shahab0Guojun Zheng1Fahad M. Alshabrmi2Mohammed Bourhia3Gezahign Fentahun Wondmie4Ahmad Mohammad Salamatullah5State Key Laboratories of Chemical Resources Engineering Beijing University of Chemical Technology, Beijing, ChinaState Key Laboratories of Chemical Resources Engineering Beijing University of Chemical Technology, Beijing, ChinaDepartment of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah, Saudi ArabiaDepartment of Chemistry and Biochemistry, Faculty of Medicine and Pharmacy, Ibn Zohr University, Agadir, MoroccoDepartment of Biology, College of Science, Bahir Dar University, Bahir Dar, EthiopiaDepartment of Food Science and Nutrition, College of Food and Agricultural Sciences, King Saud University, Riyadh, Saudi ArabiaAldose reductase (AR) is an important target in the development of therapeutics against hyper-glycemia-induced health complications such as retinopathy, etc. In this study, we employed a combination of structure-based drug design, molecular simulation, and free energy calculation approaches to identify potential hit molecules against anti-diabetic (anti-hyperglycemic)-induced health complications. The 3D structure of aldoreductase was screened for multiple compound libraries (1,00,000 compounds) and identified as ZINC35671852, ZINC78774792 from the ZINC database, Diamino-di nitro-methyl dioctyl phthalate, and Penta-o-galloyl-glucose from the South African natural compounds database, and Bisindolylmethane thiosemi-carbazides and Bisindolylme-thane-hydrazone from the Inhouse database for this study. The mode of binding interactions of the selected compounds later predicted their aldose reductase inhibitory potential. These com-pounds interact with the key active site residues through hydrogen bonds, salt bridges, and π-π interactions. The structural dynamics and binding free energy results further revealed that these compounds possess stable dynamics with excellent binding free energy scores. The structures of the lead inhibitors can serve as templates for developing novel inhibitors, and in vitro testing to confirm their anti-diabetic potential is warranted. The current study is the first to design small molecule inhibitors for the aldoreductase protein that can be used in the development of therapeutic agents to treat diabetes.https://www.frontiersin.org/articles/10.3389/fmolb.2023.1271569/fullaldose reductasediabetes melitusSBVSmolecular docking simulationMMGBSA |
| spellingShingle | Muhammad Shahab Guojun Zheng Fahad M. Alshabrmi Mohammed Bourhia Gezahign Fentahun Wondmie Ahmad Mohammad Salamatullah Exploring potent aldose reductase inhibitors for anti-diabetic (anti-hyperglycemic) therapy: integrating structure-based drug design, and MMGBSA approaches Frontiers in Molecular Biosciences aldose reductase diabetes melitus SBVS molecular docking simulation MMGBSA |
| title | Exploring potent aldose reductase inhibitors for anti-diabetic (anti-hyperglycemic) therapy: integrating structure-based drug design, and MMGBSA approaches |
| title_full | Exploring potent aldose reductase inhibitors for anti-diabetic (anti-hyperglycemic) therapy: integrating structure-based drug design, and MMGBSA approaches |
| title_fullStr | Exploring potent aldose reductase inhibitors for anti-diabetic (anti-hyperglycemic) therapy: integrating structure-based drug design, and MMGBSA approaches |
| title_full_unstemmed | Exploring potent aldose reductase inhibitors for anti-diabetic (anti-hyperglycemic) therapy: integrating structure-based drug design, and MMGBSA approaches |
| title_short | Exploring potent aldose reductase inhibitors for anti-diabetic (anti-hyperglycemic) therapy: integrating structure-based drug design, and MMGBSA approaches |
| title_sort | exploring potent aldose reductase inhibitors for anti diabetic anti hyperglycemic therapy integrating structure based drug design and mmgbsa approaches |
| topic | aldose reductase diabetes melitus SBVS molecular docking simulation MMGBSA |
| url | https://www.frontiersin.org/articles/10.3389/fmolb.2023.1271569/full |
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