ChemPLAN-Net: A deep learning framework to find novel inhibitor fragments for proteins

Abstract

Fragment-based drug design plays an important role in the drug discovery process by reducing the complex small-molecule space into a more manageable fragment space. We leverage the power of deep learning to design ChemPLAN-Net; a model that incorporates the pairwise association of physicochemical features of both the protein drug targets and the inhibitor and learns from thousands of protein co-crystal structures in the PDB database to predict previously unseen inhibitor fragments. Our novel protocol handles the computationally challenging multi-label, multi-class problem, by defining a fragment database and using an iterative featurepair binary classification approach. By training ChemPLAN-Net on available co-crystal structures of the protease protein family, excluding HIV-1 protease as a target, we are able to outperform fragment docking and recover the target’s inhibitor fragments found in co-crystal structures or identified by in-vitro cell assays.