Computational Analysis of ZINC Analogues for Antidiabetic Phytochemical with Inhibitory Activity against Aldose Reductase Enzyme

Abstract

The pathognomonic role of sorbitol pathway in the development of microvascular complications cannot go underappreciated; while it may not be a sole independent initiator, it remains a key contributor to the initiation and progression of diabetic microangiopathies, particularly retinopathy, neuropathy, and nephropathy. The sorbitol pathway is a two-step reaction process initiated by the rate-limiting enzyme aldose reductase. This study aimed to screen ZINC databases for chemical compounds similar to Ellagic acid, Kaempferol, and Mangiferin and analyze their pharmacokinetic, toxicological and docking profile using computational methods. These phytochemicals were chosen based on literature review of ethnobotanical studies and validated via SwissTargetPrediction.
An in-silico study design was employed using computational algorithms. Molecular structures of analogues were obtained from
ZINC database and prepared using Avogadro software. Docking analysis was carried out using AutoDock Vina embedded in Chimera. Visualization of ligand-enzyme interactions was done using Discovery studio. SWISSADME and Protox-II were used to profile pharmacokinetic and toxicity of the analogs. A total of 44 analogs were analyzed. Sulindac and parent phytochemicals were used as comparators. Kaempferol had strongest binding affinity (-8.7) followed by Ellagic acid and Mangiferin tying at -8.4. Kaempferol analogs had highest binding affinity compared to analogues of Ellagic acid and Mangiferin. In terms of Pharmacokinetic profile, analogues of Ellagic acid demonstrated
a favorable profile with no Lipinski rule violations, high GI absorption, and inhibition limited to CYP1A2, which plays a minor role in drug metabolism compared to other enzymes. Toxicology predictions indicated that Kaempferol exhibited a higher safety profile compared to Ellagic acid and Mangiferin, with LD50 values of 3919 mg/kg, 2991 mg/kg, and 2 mg/kg, respectively. Ellagic acid analogues demonstrated chemical safety, absence of mutagenicity, hepatotoxicity, cytotoxicity, and activation of
various pathways. Among the Kaempferol analogues, a subset was potentially carcinogenic and mutagenic, while all exhibited potential pathway activation. Mangiferin analogues, except for a few compounds, did not activate specific pathways, nor did they
demonstrate hepatotoxicity or cytotoxicity. However, some analogues exhibited potential immunogenicity and mutagenicity.
Kaempferol and some of its ZINC analogues had strongest binding affinity compared to Ellagic acid, Mangiferin and their analogues. This can be attributed to the simpler structure of Kaempferol, allowing it to fit snugly into the hydrophobic pocket of aldose reductase. Ellagic acid, with its planar and rigid structure, interacted primarily with the outer surface of the hydrophobic pocket. Similarly, due to its complex and large structure, Mangiferin demonstrated a relatively lower affinity. Analogues ZINC000005004393, ZINC000003872446, and ZINC000031156069 for Kaempferol, Ellagic acid, and Mangiferin respectively depicted the best optimal characteristics required for further development. We recommend an in vitro study be conducted to assess and validate the claims arrived at in this study