Neural networks prediction of the protein-ligand binding affinity with circular fingerprints

BACKGROUND: Protein-ligand binding affinity is of significant importance in structure-based drug design. Recently, the development of machine learning techniques has provided an efficient and accurate way to predict binding affinity. However, the prediction performance largely depends on how molecules are represented. OBJECTIVE: Different molecular descriptors are designed to capture different features. The study aims to identify the optimal circular fingerprints for predicting protein-ligand binding affinity with matched neural network architectures. METHODS: Extended-connectivity fingerprints (ECFP) and protein-ligand extended connectivity fingerprints (PLEC) encode circular atomic and bonding connectivity environments with the preference for intra- and inter-molecular features, respectively. Densely-connected neural networks are employed to map the circular fingerprints of protein-ligand complexes to binding affinities RESULTS: The performance of neural networks is sensitive to the parameters used for ECFP and PLEC fingerprints. The R2_score of the evaluated ECFP and PLEC fingerprints reaches 0.52 and 0.49, higher than that of the improperly set ECFP and PLEC fingerprints with R2_score of 0.45 and 0.38, respectively. Additionally, compared to the predictions from the standalone fingerprints, the ECFP+PLEC conjoint ones slightly improve the prediction accuracy with R2_score of approximately 0.55. CONCLUSION: Both intra- and inter-molecular structural features encoded in the circular fingerprints contribute to the protein-ligand binding affinity. Optimizing the parameters of ECFP and PLEC can enhance performance. The conjoint fingerprint scheme can be generally extended to other molecular descriptors for enhanced feature engineering and improved predictive performance.