Theoretical and Computational Chemistry

Molecular Optimization by Capturing Chemist’s Intuition Using Deep Neural Networks


A main challenge in drug discovery is finding molecules with a desirable balance of multiple properties. Here, we focus on the task of molecular optimization, where the goal is to optimize a given starting molecule towards desirable properties. This task can be framed as a machine translation problem in natural language processing, where in our case, a molecule is translated into a molecule with optimized properties based on the SMILES representation. Typically, chemists would use their intuition to suggest chemical transformations for the starting molecule being optimized. A widely used strategy is the concept of matched molecular pairs where two molecules differ by a single transformation. We seek to capture the chemist's intuition from matched molecular pairs using machine translation models. Specifically, the sequence-to-sequence model with attention mechanism, and the Transformer model are employed to generate molecules with desirable properties. As a proof of concept, three ADMET properties are optimized simultaneously: logD, solubility, and clearance, which are important properties of a drug. Since desirable properties often vary from project to project, the user-specified desirable property changes are incorporated into the input as an additional condition together with the starting molecules being optimized. Thus, the models can be guided to generate molecules satisfying the desirable properties. Additionally, we compare the two machine translation models based on the SMILES representation, with a graph-to-graph translation model HierG2G, which has shown the state-of-the-art performance in molecular optimization. Our results show that the Transformer can generate more molecules with desirable properties by making small modifications to the given starting molecules, which can be intuitive to chemists. A further enrichment of diverse molecules can be achieved by using an ensemble of models.


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Supplementary material

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molecular optimization transformer supplementary

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