The hit-to-lead process makes the physicochemical properties of the hit molecules that show the desired type of activity obtained in the screening assay more drug-like. Deep learning-based molecular generative models are expected to contribute to the hit-to-lead process. The simplified molecular input line entry system (SMILES), which is a string of alphanumeric characters representing the chemical structure of a molecule, is one of the most commonly used representations of molecules, and molecular generative models based on SMILES have achieved significant success. However, in contrast to molecular graphs, during the process of generation, SMILES are not considered as valid SMILES. Further, it is quite difficult to generate molecules starting from a certain molecule, thus making it difficult to apply SMILES to the hit-to-lead process. In this study, we have developed a SMILES-based generative model that can be generated starting from a certain molecule. This method generates partial SMILES and inserts it into the original SMILES using Monte Carlo Tree Search and a Recurrent Neural Network. We validated our method using a molecule dataset obtained from the ZINC database and successfully generated molecules that were both well optimized for the objectives of the quantitative estimate of drug-likeness (QED) and penalized octanol-water partition coefficient (PLogP) optimization. The source code is available at https://github.com/sekijima-lab/mermaid.

<div>The hit-to-lead process makes the physicochemical properties of the hit compounds that show the desired type of activity obtained in the screening assay more drug-like. Deep learning-based molecular generative models are expected to contribute to the hit-to-lead process.</div><div>The simplified molecular input line entry system (SMILES), which is a string of alphanumeric characters representing the chemical structure of a molecule, is one of the most commonly used representations of molecules, and molecular generative models based on SMILES have achieved significant success. However, in contrast to molecular graphs, during the process of generation, SMILES are not considered as valid SMILES. Further, it is quite difficult to generate molecules starting from a certain molecule, thus making it difficult to apply SMILES to the hit-to-lead process.In this study, we have developed a SMILES-based generative model that can be generated starting from a certain compound. This method generates partial SMILES and inserts it into the original SMILES using Monte Carlo Tree Search and a Recurrent Neural Network.We validated our method using a molecule dataset obtained from the ZINC database and successfully generated molecules that were both well optimized for the objectives of the quantitative estimate of drug-likeness (QED) and penalized octanol-water partition coefficient (PLogP) optimization.</div><div>The source code is available at https: //github.com/sekijima-lab/mermaid.</div>

<div>The hit-to-lead process makes the physicochemical properties of the hit compounds that show the desired type of activity obtained in the screening assay more drug-like. Deep learning-based molecular generative models are expected to contribute to the hit-to-lead process.</div><div>The simplified molecular input line entry system (SMILES), which is a string of alphanumeric characters representing the chemical structure of a molecule, is one of the most commonly used representations of molecules, and molecular generative models based on SMILES have achieved significant success. However, in contrast to molecular graphs, during the process of generation, SMILES are not considered as valid SMILES. Further, it is quite difficult to generate molecules starting from a certain molecule, thus making it difficult to apply SMILES to the hit-to-lead process.In this study, we have developed a SMILES-based generative model that can be generated starting from a certain compound. This method generates partial SMILES and inserts it into the original SMILES using Monte Carlo Tree Search and a Recurrent Neural Network.We validated our method using a molecule dataset obtained from the ZINC database and successfully generated molecules that were both well optimized for the objectives of the quantitative estimate of drug-likeness (QED) and penalized octanol-water partition coefficient (PLogP) optimization.</div><div>The source code is available at https: //github.com/sekijima-lab/mermaid.</div>

Automatic optimization methods for compounds in the vast compound space are important for drug discovery and material design. Several machine learning-based molecular generative models for drug discovery have been proposed, but most of these methods generate compounds from scratch and are not suitable for exploring and optimizing around arbitrary compounds. In this study, we developed a compound optimization method based on molecular graphs using deep reinforcement learning. This method searches for compounds on a fragment-by-fragment basis and at high density by generating fragments to be added atom by atom. Experimental results confirmed that the QED, the optimization target set in this study, was enhanced by searching around the starting compound. This means that the generated compounds are structurally similar to the starting compounds, indicating that the method is suitable for starting generation from a given compound. The source code is available at https://github.com/sekijima-lab/GARGOYLES.