ABSTRACT
The prerequisite of therapeutic drug design and discovery is to identify novel molecules and developing lead candidates with desired biophysical and biochemical properties. Deep generative models have demonstrated their ability to find such molecules by exploring a huge chemical space efficiently. An effective way to generate new molecules with desired target properties is by constraining the critical fucntional groups or the core scaffolds in the generation process. To this end, we developed a domain aware generative framework called 3D-Scaffold that takes 3D coordinates of the desired scaffold as an input and generates 3D coordinates of novel therapeutic candidates as an output while always preserving the desired scaffolds in generated structures. We demonstrated that our framework generates predominantly valid, unique, novel, and experimentally synthesizable molecules that have drug-like properties similar to the molecules in the training set. Using domain specific data sets, we generate covalent and noncovalent antiviral inhibitors targeting viral proteins. To measure the success of our framework in generating therapeutic candidates, generated structures were subjected to high throughput virtual screening via docking simulations, which shows favorable interaction against SARS-CoV-2 main protease (Mpro) and nonstructural protein endoribonuclease (NSP15) targets. Most importantly, our deep learning model performs well with relatively small 3D structural training data and quickly learns to generalize to new scaffolds, highlighting its potential application to other domains for generating target specific candidates.