Comparative Analysis of Hepatitis C virus Genotype 1a (Isolate 1) using Multiple Regression Algorithms and Fingerprinting Techniques
Authors: Nur Fiat Daffa , Suratinoyo Syifabela , Kolang Indri Claudia , Ticoalu Injilia Tirza , Purnomo Nadira Tri Ardianti , Mawara Reza Michelly Cantika , Sengkey Daniel , Masengi Angelina Stevany Regina , Sambul Alwin Melkie 
Published: September 2024

Approximately 70 million people worldwide have been infected with Hepatitis C virus (HCV), presenting a critical global health challenge. As a member of the Flaviviridae family, HCV can cause severe liver diseases such as cirrhosis, acute hepatitis, and chronic hepatitis. The Hepatitis C virus (HCV) genome encodes a single polyprotein consisting of 3010 amino acids, which when processed contains 10 polypeptides derived from cellular and viral proteases. These include structural proteins such as core protein, E1 and E2 envelope glycoproteins, and nonstructural proteins such as NS1, NS2, NS3, NS4A, NS4B, NS5A, and NS5B. Nonstructural proteins will be released by HCV NS2-3 and NS3-4A proteases, however, structural proteins will be released by host ER signaling peptidases. co-translationally and post-translationally form 10 individual structural proteins: 5'-C-E1-E2-p7-NS2-NS3-NS4A-NS4B-NS5A-NS5B-3'. Despite extensive research, there are significant gaps in predictive and analytical approaches to managing HCV, particularly in understanding the polyprotein structure and its implications for drug discovery. This study addresses these gaps by employing machine learning techniques to analyze HCV polyprotein using various fingerprinting methods and regression algorithms. The data was sourced from the ChEMBL database, and fingerprinting techniques such as PubChem, MACCS, and E-State were utilized. Regression algorithms, including Gradient Boosting Regression (GBR), Random Forest Regression (RFR), AdaBoost Regression (ABR), and Hist Gradient Boosting Regression (HSR), were applied. Model performance was evaluated using R² and Adjusted R² metrics, comparing default models with those enhanced by hyperparameter tuning. Feature importance analysis was conducted to identify key features influencing model performance, aiding in model simplification. The results show that although hyperparameter tuning does not significantly improve the predictive power of a model, it can provide an insight into model optimization. In particular, the default model showed higher R² and Adjusted R² values across different fingerprinting techniques compared to models with hyperparameterized features. Gradient Boosting Regression (GBR) and Random Forest Regression (RFR) consistently performed well, with GBR showing the highest R² values when using PubChem fingerprints. Although there was no significant improvement through hyperparameter tuning, this study was able to find out the features that strongly influenced the model performance by conducting a feature importance analysis. This analysis helped simplify the model and highlighted the potential of machine learning in improving the understanding of HCV polyprotein structure. This research identifies optimal regression models and fingerprinting techniques, providing a strong framework for future drug discovery efforts aimed at improving global health outcomes. The research also shows that it is important to date to advance drug discovery using machine learning.