Artificial Intelligent Deep Learning Molecular Generative Modeling of Scaffold-Focused and Cannabinoid CB2 Target-Specific Small-Molecule Sublibraries
Abstract
Design and generation of high-quality target- and scaffold-specific small molecules is an important strategy for the discovery of unique and potent bioactive drug molecules. To achieve this goal, authors have developed the deep-learning molecule generation model (DeepMGM) and applied it for the de novo molecular generation of scaffold-focused small-molecule libraries. In this study, a recurrent neural network (RNN) using long short-term memory (LSTM) units was trained with drug-like molecules to result in a general model (g-DeepMGM). Sampling practices on indole and purine scaffolds illustrate the feasibility of creating scaffold-focused chemical libraries based on machine intelligence. Subsequently, a target-specific model (t-DeepMGM) for cannabinoid receptor 2 (CB2) was constructed following the transfer learning process of known CB2 ligands. Sampling outcomes can present similar properties to the reported active molecules. Finally, a discriminator was trained and attached to the DeepMGM to result in an in silico molecular design-test circle. Medicinal chemistry synthesis and biological validation was performed to further investigate the generation outcome, showing that XIE9137 was identified as a potential allosteric modulator of CB2. This study demonstrates how recent progress in deep learning intelligence can benefit drug discovery, especially in de novo molecular design and chemical library generation.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Mar 07, 2022
- Source ID
- 10.3390/cells11050915
Entities
People
- Xiang-Qun Xie
- Yuemin Bian
Organizations
- National Institute on Drug Abuse
- United States Department of Defense