MFPLI: A Computational Framework for Assessing Biological Authenticity of Protein-Ligand Interactions Using Molecular Fingerprints and Structural Features

Abstract

Traditional computational drug discovery approaches struggle to accurately evaluate the biological authenticity of protein-ligand binding conformations due to inherent limitations in empirical scoring functions and force field approximations. This study proposes MFPLI - a deep learning framework integrating multimodal physicochemical features to systematically assess the biological authenticity alignment between molecular docking poses and true co-crystal structures. By establishing a continuous surface characterization system for protein-ligand interfaces, we concurrently incorporate geometric curvature features (radius, shape index) and chemical interaction fields (electrostatic potential, hydrogen-bond networks, hydrophobicity gradients). A contrastive learning architecture based on Siamese equivariant graph neural networks was developed to enable discriminative analysis between co-crystal conformations and parameter-perturbed pseudo-conformations generated through inverse docking. The five-channel fusion model demonstrates robust performance on the time-split PoseBuster validation set (AUC=0.91), with predicted Euclidean distance deviation ({Delta}E) effectively distinguishing native co-crystal conformations from aberrant docking poses in 80% of samples. Notably, 71% of {Delta}E-negative samples concentrate within the [-0.3, 0] interval, reflecting physical consistency between model predictions and conformational transition processes. This framework establishes a novel paradigm for biological authenticity assessment in virtual screening for computer-aided drug discovery through synergistic modeling of surface topology and interaction chemistry.