Graph Convolutional Capsule Regression (GCCR): A Model for Accelerated Filtering of Novel Potential Candidates for SARS-CoV-2 based on Binding Affinity.

Background: There has been a growing interest in discovering a viable drug for the new coronavirus (SARS-CoV-2) since the beginning of the pandemic. Protein-ligand interaction studies are a crucial step in the drug discovery process, as it helps us narrow the search space for potential ligands with high drug-likeness. Derivatives of popular drugs like Remdesivir generated through tools employing evolutionary algorithms are usually considered potential candidates. However, screening promising molecules from such a large search space is difficult. In a conventional screening process, for each ligand-target pair, there are time-consuming interaction studies that use docking simulations before downstream tasks like thermodynamic, kinetic, and electrostatic-potential evaluation.

Objective: This work aims to build a model based on deep learning applied over the graph structure of the molecules to accelerate the screening process for novel potential candidates for SARS-CoV-2 by predicting the binding energy of the protein-ligand complex.

Methods: In this work, 'Graph Convolutional Capsule Regression' (GCCR), a model which uses Capsule Neural Networks (CapsNet) and Graph Convolutional Networks (GCN) to predict the binding energy of a protein-ligand complex is being proposed. The model's predictions were further validated with kinetic and free energy studies like Molecular Dynamics (MD) for kinetic stability and MM/GBSA analysis for free energy calculations.

Results: The GCCR showed an RMSE value of 0.0978 for 81.3% of the concordance index. The RMSE of GCCR converged around the iteration of just 50 epochs scoring a lower RMSE than GCN and GAT. When training with Davis Dataset, GCCR gave an RMSE score of 0.3806 with a CI score of 87.5%.

Conclusion: The proposed GCCR model shows great potential in improving the screening process based on binding affinity and outperforms baseline machine learning models like DeepDTA, KronRLS, Sim- Boost, and other Graph Neural Networks (GNN) based models like Graph Convolutional Networks (GCN) and Graph Attention Networks (GAT).