Theoretical and Computational Chemistry

A Bag of Tricks for Automated De Novo Design of Molecules with the Desired Properties: Application to EGFR Inhibitor Discovery


Deep generative neural networks have been used increasingly in computational chemistry for de novo design of molecules with desired properties. Many deep learning approaches employ reinforcement learning for optimizing the target properties of the generated molecules. However, the success of this approach is often hampered by the problem of sparse rewards as the majority of the generated molecules are expectedly predicted as inactives. We propose several technical innovations to address this problem and improve the balance between exploration and exploitation modes in reinforcement learning. In a proof-of-concept study, we demonstrate the application of the deep generative recurrent neural network enhanced by several novel technical tricks to designing experimentally validated potent inhibitors of the epidermal growth factor (EGFR). The proposed technical solutions are expected to substantially improve the success rate of finding novel bioactive compounds for specific biological targets using generative and reinforcement learning approaches.


Thumbnail image of egfr_manuscript_final.pdf

Supplementary material

Thumbnail image of egfr_supplementary.pdf
egfr supplementary