AlzyFinder: A Machine-Learning-Driven Platform for Ligand-Based Virtual Screening and Network Pharmacology.

Abstract

Alzheimer's disease (AD), a prevalent neurodegenerative disorder, presents significant challenges in drug development due to its multifactorial nature and complex pathophysiology. The AlzyFinder Platform, introduced in this study, addresses these challenges by providing a comprehensive, free web-based tool for parallel ligand-based virtual screening and network pharmacology, specifically targeting over 85 key proteins implicated in AD. This innovative approach is designed to enhance the identification and analysis of potential multitarget ligands, thereby accelerating the development of effective therapeutic strategies against AD. AlzyFinder Platform incorporates machine learning models to facilitate the ligand-based virtual screening process. These models, built with the XGBoost algorithm and optimized through Optuna, were meticulously trained and validated using robust methodologies to ensure high predictive accuracy. Validation included extensive testing with active, inactive, and decoy molecules, demonstrating the platform's efficacy in distinguishing active compounds. The models are evaluated based on balanced accuracy, precision, and F1 score metrics. A unique soft-voting ensemble approach is utilized to refine the classification process, integrating the strengths of individual models. This methodological framework enables a comprehensive analysis of interaction data, which is presented in multiple formats such as tables, heat maps, and interactive Ligand-Protein Interaction networks, thus enhancing the visualization and analysis of drug-protein interactions. AlzyFinder was applied to screen five molecules recently reported (and not used to train or validate the ML models) as active compounds against five key AD targets. The platform demonstrated its efficacy by accurately predicting all five molecules as true positives with a probability greater than 0.70. This result underscores the platform's capability in identifying potential therapeutic compounds with high precision. In conclusion, AlzyFinder's innovative approach extends beyond traditional virtual screening by incorporating network pharmacology analysis, thus providing insights into the systemic actions of drug candidates. This feature allows for the exploration of ligand-protein and protein-protein interactions and their extensions, offering a comprehensive view of potential therapeutic impacts. As the first open-access platform of its kind, AlzyFinder stands as a valuable resource for the AD research community, available at http://www.alzyfinder-platform.udec.cl with supporting data and scripts accessible via GitHub https://github.com/ramirezlab/AlzyFinder.