Identification of Putative Plant-Based ALR-2 Inhibitors to Treat Diabetic Peripheral Neuropathy

Mohd Saeed; Munazzah Tasleem; Ambreen Shoib; Mohd Adnan Kausar; Abdel Moneim E Sulieman; Nadiyah M Alabdallah; Zeina El Asmar; Abdelmuhsin Abdelgadir; Asma Al-Shammary; Md Jahoor Alam; Riadh Badroui; Maryam Zahin

doi:10.3390/cimb44070194

Identification of Putative Plant-Based ALR-2 Inhibitors to Treat Diabetic Peripheral Neuropathy

Curr Issues Mol Biol. 2022 Jun 29;44(7):2825-2841. doi: 10.3390/cimb44070194.

Authors

Affiliations

¹ Department of Biology, College of Sciences, University of Ha'il, P.O. Box 2240, Ha'il 81451, Saudi Arabia.
² School of Electronic Science and Engineering, University of Electronic Science and Technology of China, Chengdu 610054, China.
³ Department of Clinical Pharmacy, College of Pharmacy, Jazan University, P.O. Box 114, Jazan 45142, Saudi Arabia.
⁴ Department of Biochemistry, College of Medicine, University of Ha'il, P.O. Box 2240, Ha'il 81451, Saudi Arabia.
⁵ Department of Biology, College of Science, Imam Abdulrahman Bin Faisal University, P.O. Box 1982, Dammam 31441, Saudi Arabia.
⁶ Department of Public Health, College of Public Health and Health Informatics, University of Ha'il, P.O. Box 2240, Ha'il 81451, Saudi Arabia.
⁷ Section of Histology-Cytology, Medicine Faculty of Tunis, University of Tunis El Manar, Tunis 1007, Tunisia.
⁸ James Graham Brown Cancer Center, University of Louisville, Louisville, KY 4020, USA.

Abstract

Diabetic peripheral neuropathy (DPN) is a common diabetes complication (DM). Aldose reductase -2 (ALR-2) is an oxidoreductase enzyme that is most extensively studied therapeutic target for diabetes-related complications that can be inhibited by epalrestat, which has severe adverse effects; hence the discovery of potent natural inhibitors is desired. In response, a pharmacophore model based on the properties of eplarestat was generated. The specified pharmacophore model searched the NuBBE_DB database of natural compounds for prospective lead candidates. To assess the drug-likeness and ADMET profile of the compounds, a series of in silico filtering procedures were applied. The compounds were then put through molecular docking and interaction analysis. In comparison to the reference drug, four compounds showed increased binding affinity and demonstrated critical residue interactions with greater stability and specificity. As a result, we have identified four potent inhibitors: ZINC000002895847, ZINC000002566593, ZINC000012447255, and ZINC000065074786, that could be used as pharmacological niches to develop novel ALR-2 inhibitors.

Keywords: ADMET; NuBBEDB; molecular docking; pharmacophore; structure-based drug design.

Grants and funding

RG-20 137/University of hail