Identification of Potential Aldose Reductase Inhibitors Using Convolutional Neural Network-Based in Silico Screening

Abstract

Aldose reductase (ALR2) is a notable enzyme of the polyol pathway responsible for aggravating diabetic neuropathy complications. The first step begins when it catalyzes the reduction of glucose to sorbitol with NADPH as a coenzyme. Elevated concentrations of sorbitol damage the tissues, leading to complications like neuropathy. Though considerable effort has been pushed toward the successful discovery of potent inhibitors, its discovery still remains an elusive task. To this end, we present a 3D convolutional neural network (3D-CNN) based ALR2 inhibitor classification technique by dealing with snapshots of images captured from 3D chemical structures with multiple rotations as input data. The CNN-based architecture was trained on the 360 sets of image data along each axis and further prediction on the Maybridge library by each of the models. Subjecting the retrieved hits to molecular docking leads to the identification of the top 10 molecules with high binding affinity. The hits displayed a better blood− brain barrier penetration (BBB) score (90% with more than four scores) as compared to standard inhibitors (38%), reflecting the superior BBB penetrating efficiency of the hits. Followed by molecular docking, the biological evaluation spotlighted five compounds as promising ALR2 inhibitors and can be considered as a likely prospect for further structural optimization with medicinal chemistry efforts to improve their inhibition efficacy and consolidate them as new ALR2 antagonists in the future. In addition, the study also demonstrated the usefulness of scaffold analysis of the molecules as a method for investigating the significance of structurally diverse compounds in data-driven studies. For reproducibility and accessibility purposes, all of the source codes used in our study are publicly available.

From NMR to AI: Designing a Novel Chemical Representation to Enhance Machine Learning Predictions of Physicochemical Properties

“…By guiding the selection of molecular descriptors, NMR has enhanced the accuracy and reliability of ML predictions, underscoring its value in complex biological analyses . Additionally, the employment of NMR-derived structural insights in 3D convolutional neural network (3D-CNN) models for drug discovery, particularly in the evaluation of aldose reductase inhibitors, has demonstrated the potential of NMR to contribute significantly to the robustness and accuracy of molecular interaction predictions and efficacy assessments …”