PharmacoNet: Accelerating Large-Scale Virtual Screening by Deep Pharmacophore Modeling

As the size of accessible compound libraries expands to over 10 billion, the need for more efficient structure-based virtual screening methods is emerging. Different pre-screening methods have been developed to rapidly screen the library, but the structure-based methods applicable to general proteins are still lacking: the challenge is to predict the binding pose between proteins and ligands and perform scoring in an extremely short time. We introduce PharmacoNet, a deep learning framework that identifies the optimal 3D pharmacophore arrangement which a ligand should have for stable binding from the binding site. By coarse-grained graph matching between ligands and the generated pharmacophore arrangement, we solve the expensive binding pose sampling and scoring procedures of existing methods in a single step. PharmacoNet is significantly faster than state-of-the-art structure-based approaches, yet reasonably accurate with a simple scoring function. Furthermore, we show the promising result that PharmacoNet effectively retains hit candidates even under the high pre-screening filtration rates. Overall, our study uncovers the hitherto untapped potential of a pharmacophore modeling approach in deep learning-based drug discovery.

Fragment-based molecular generative model with high generalization ability and synthetic accessibility

Deep generative models are attracting great attention for molecular design with desired properties. Most existing models generate molecules by sequentially adding atoms. This often renders generated molecules with less correlation with target properties and low synthetic accessibility. Molecular fragments such as functional groups are more closely related to molecular properties and synthetic accessibility than atoms. Here, we propose a fragment-based molecular generative model which designs new molecules with target properties by sequentially adding molecular fragments to any given starting molecule. A key feature of our model is a high generalization ability in terms of property control and fragment types. The former becomes possible by learning the contribution of individual fragments to the target properties in an auto-regressive manner. For the latter, we used a deep neural network that predicts the bonding probability of two molecules from the embedding vectors of the two molecules as input. The high synthetic accessibility of the generated molecules is implicitly considered while preparing the fragment library with the BRICS decomposition method. We show that the model can generate molecules with the simultaneous control of multiple target properties at a high success rate. It also works equally well with unseen fragments even in the property range where the training data is rare, verifying the high generalization ability. As a practical application, we demonstrated that the model can generate potential inhibitors with high binding affinities against the 3CL protease of SARS-COV-2 in terms of docking score.