D3Rings: A Fast and Accurate Method for Ring System Identification and Deep Generation of Drug-Like Cyclic Compounds.

Abstract

Continuous exploration of the chemical space of molecules to find ligands with high affinity and specificity for specific targets is an important topic in drug discovery. A focus on cyclic compounds, particularly natural compounds with diverse scaffolds, provides important insights into novel molecular structures for drug design. However, the complexity of their ring structures has hindered the applicability of widely accepted methods and software for the systematic identification and classification of cyclic compounds. Herein, we successfully developed a new method, D3Rings, to identify acyclic, monocyclic, spiro ring, fused and bridged ring, and cage ring compounds, as well as macrocyclic compounds. By using D3Rings, we completed the statistics of cyclic compounds in three different databases, e.g., ChEMBL, DrugBank, and COCONUT. The results demonstrated the richness of ring structures in natural products, especially spiro, macrocycles, and fused and bridged rings. Based on this, three deep generative models, namely, VAE, AAE, and CharRNN, were trained and used to construct two data sets similar to DrugBank and COCONUT but 10 times larger than them. The enlarged data sets were then used to explore the molecular chemical space, focusing on complex ring structures, for novel drug discovery and development. Docking experiments with the newly generated COCONUT-like data set against three SARS-CoV-2 target proteins revealed that an expanded compound database improves molecular docking results. Cyclic structures exhibited the best docking scores among the top-ranked docking molecules. These results suggest the importance of exploring the chemical space of structurally novel cyclic compounds and continuous expansion of the library of drug-like compounds to facilitate the discovery of potent ligands with high binding affinity to specific targets. D3Rings is now freely available at http://www.d3pharma.com/D3Rings/.