Conditional reduction of the loss value versus reinforcement learning for biassing a de-novo drug design generator.

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Abstract

Deep learning has demonstrated promising results in de novo drug design. Often, the general pipeline consists of training a generative model (G) to learn the building rules of valid molecules, then using a biassing technique such as reinforcement learning (RL) to focus G on the desired chemical space. However, this sequential training of the same model for different tasks is known to be prone to a catastrophic forgetting (CF) phenomenon. This work presents a novel yet simple approach to bias G with significantly less CF than RL. The proposed method relies on backpropagating a reduced value of the cross-entropy loss used to train G according to the proportion of desired molecules that the biased-G can generate. We named our approach CRLV, short for conditional reduction of the loss value. We compared the two biased models (RL-biased-G and CRLV-biased-G) for four different objectives related to de novo drug design.CRLV-biased-G outperformed RL-biased-G in all four objectives and manifested appreciably less CF. Besides, an intersection analysis between molecules generated by the RL-biased-G and the CRLV-biased-G revealed that they can be used jointly without losing diversity given the low percentage of overlap between the two to further increase the desirability. Finally, we show that the difficulty of an objective is proportional to (i) its frequency in the dataset used to train G and (ii) the associated structural variance (SV), which is a new parameter we introduced in this paper, calling for novel exploration techniques for such difficult objectives.© 2022. The Author(s).