Spatial Graph Attention and Curiosity-driven Policy for Antiviral Drug Discovery

Wu, Yulun; Choma, Nicholas; Chen, Andrew; Cashman, Mikaela; Prates, 'Erica T.; Shah, Manesh; Vergara, Ver'onica G. Melesse; Clyde, Austin; Brettin, Thomas S.; Jong, Wibe A. de; Kumar, Neeraj; Head, Martha S.; Stevens, Rick L.; Nugent, Peter; Jacobson, Daniel A.; Brown, James B.

We developed Distilled Graph Attention Policy Networks (DGAPNs), a curiosity-driven reinforcement learning model to generate novel graph-structured chemical representations that optimize user-defined objectives by efficiently navigating a physically constrained domain. The framework is examined on the task of generating molecules that are designed to bind, noncovalently, to functional sites of SARS-CoV-2 proteins. We present a spatial Graph Attention Network (sGAT) that leverages self-attention over both node and edge attributes as well as encoding spatial structure -- this capability is of considerable interest in areas such as molecular and synthetic biology and drug discovery. An attentional policy network is then introduced to learn decision rules for a dynamic, fragment-based chemical environment, and state-of-the-art policy gradient techniques are employed to train the network with enhanced stability. Exploration is efficiently encouraged by incorporating innovation reward bonuses learned and proposed by random network distillation. In experiments, our framework achieved outstanding results compared to state-of-the-art algorithms, while increasing the diversity of proposed molecules and reducing the complexity of paths to chemical synthesis.