Theoretical and Computational Chemistry

SMILES-Based Deep Generative Scaffold Decorator for De-Novo Drug Design


Molecular generative models trained with small sets of molecules represented as SMILES strings are able to generate large regions of the chemical space. Unfortunately, due to the sequential nature of SMILES strings, these models are not able to generate molecules given a scaffold (i.e. partially-built molecules with explicit attachment points). Herein we report a new SMILES-based molecular generative architecture that generates molecules from scaffolds and can be trained from any arbitrary molecular set. This is possible thanks to a new molecular set pre-processing algorithm that exhaustively cuts all combinations of acyclic bonds of every molecule, obtaining a large number of scaffold-decorations combinations. Moreover, it serves as a data augmentation technique and can be readily coupled with randomized SMILES to obtain even better results with small sets. Two examples showcasing the potential of the architecture in medicinal and synthetic chemistry are described: First, models were trained with a training set obtained from a small set of Dopamine Receptor D2 (DRD2) active modulators and were able to meaningfully decorate a wide range of scaffolds and obtain molecular series predicted active on DRD2. Second, a larger set of drug-like molecules from ChEMBL was selectively sliced using synthetic chemistry constraints (RECAP rules). Moreover, the resulting scaffold-decorations were filtered to only allow decorations that were fragment-like. This allowed models trained with this dataset to selectively decorate diverse scaffolds with fragments that were generally predicted to be synthesizable and attachable to the scaffold using known synthetic approaches. In both cases, the models were already able to decorate molecules using specific knowledge without the need to add it with other techniques, such as reinforcement learning. We envision that this architecture will become a useful addition to the already existent architectures for de-novo molecular generation.


Thumbnail image of smiles_based_scaffold_decorator.pdf

Supplementary material

Thumbnail image of smiles_based_scaffold_decorator_additional_methods.pdf
smiles based scaffold decorator additional methods
Thumbnail image of smiles_based_scaffold_decorator_additional_figures.pdf
smiles based scaffold decorator additional figures

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